1. Management of Type 2 Diabetes
Dr.Gayotri Goswami
Attending Physician,
Jacobi-North Central Bronx Hospital
April 29th, 2009

3. Accounts for 90-95% of all diabetes mellitus cases
Caused by a combination of complex metabolic disorders that result from co-existing defects of multiple organ sites such as insulin resistance at the adipose tissue and muscle, a progressive decline in pancreatic insulin secretion and unopposed glucagon action causing unrestrained hepatic glucose production

4. Before the appearance of clinical symptoms a degree of hyperglycemia may be present, causing pathologic and functional changes in various target tissue
Most affected individuals are obese with varying degrees of insulin resistance while the non obese may have a percentage of visceral fat which can also cause insulin resistance

5. Stages of Type 2 Diabetes Related to Beta-Cell Function
100 75
Beta­Cell Function (%) 50
Type 2 Phase 1
IGT
Type 2 Phase 3 25
Postprandial Hyperglycemia
Stages of Type 2 Diabetes Related to Beta-Cell Function
Beta-cell Function from 0 to 6 years post-diagnosis appear as data points extracted from UKPDS data
Hyperglycemia in Type 2 diabetes is associated with a decline in Beta-cell function. Insulin deficiency ultimately causes reduced insulin-mediated glucose uptake from muscle, exaggerated glucose production from the liver, and increased free fatty acid mobilization from adipose tissue. The result initially is postprandial hyperglycemia, which later is followed by fasting hyperglycemia.
Insulin resistance, whether genetic or acquired, can contribute to the development of Type 2 diabetes by increasing the requirements for insulin, thus leading to insulin insufficiency in those individuals whose ß cells have limited secretory reserve.
Key words:
Type 2
Beta cell
UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UKPDS. Diabetes. 1995;44:
Adapted from Lebovitz HE. Insulin secretagogues: old and new. Diabetes Reviews. 1999;7(3).
Type 2 Phase 2
­12
­10 ­6 ­2 2 6 10 14
Years from Diagnosis
Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

7. HIV therapy and Diabetes Risk
The use of combination antiretroviral therapy has yielded dramatic clinical benefits with a decrease in mortality and morbidity from HIV and its complications
These advantages have come at the price of increased incidence of unanticipated adverse metabolic effects, including insulin resistance, diabetes, dyslipidemia and lipodystrophy

8. Antiretrovirals and diabetes
Elegant studies have demonstrated that rapid development of insulin resistance and concurrent impairment of insulin secretion occurs following exposure to PI
Mechanism appears to involve a defect in glucose transport
Studies have also shown that switching patient to other regimens improved the adverse metabolic effects
Schutt et al.J.Endocrinol.183: ,2004

9. Antiretrovirals and diabetes
Risk factors for development of insulin resistance in PI treated patients are:
- positive family history of diabetes
- weight gain
- lipodystrophy
- older age
- co-infection with hepatitis C
Dagogo et al.Clinical Diabetes,2006 p

10. Antiretrovirals and diabetes
Nucleoside analogs (reverse transcriptase inhibitors) – stavudine,zidovudine and didanosine were associated with significantly higher risk of incident diabetes than were other agents, including PIs
Emerging data link nucleoside analogs to insulin resistance, lipodystrophy and mitochondrial dysfunction
The authors make the distinction that PI confer acute metabolic risks while the nucleoside analogs confer cumulative risks
Diabetes care, vol 31,(6), June 2008

11. IS NOT JUST TREATING HYPERGLYEMIA
TREATMENT OF T2 DM
IS NOT JUST TREATING HYPERGLYEMIA
PREVENTION AND TREATMENT OF
MACROVASCULAR DISEASE
REQUIRES ADDRESSING ALL
CARDIOVASCULAR RISK FACTORS

12. Good Glycemic Control (Lower HbA1c) Reduces Complications
DCCT
9  7%
76%
54%
60%
41%*
Kumamoto
9  7%
69%
70% -
UKPDS
8  7%
17-21%
24-33% -
16%*
HbA1c
Retinopathy
Nephropathy
Neuropathy
Macrovascular
disease
This reduction in HbA1c was associated with significant reductions in microvascular disease.
In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely.
The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant, but arguably clinically significant.
* not statistically significant
UKPDS Study Group: Lancet 352:837-53, 1998
Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995
DCCT Study Group: N Engl J Med 329:977-86, 1993

14. Targets for Glycemic Control*
Normal
Goal
American Diabetes Association1
A1C (%)
Preprandial plasma glucose (mg/dL)
Peak postprandial plasma glucose (mg/dL)
<6.0
<110
<7.0
90-130
<180
European Diabetes Policy Group2
Postprandial glucose (mg/dL)
<6.5
<135
American Association of Clinical Endocrinologists3
<140
Targets for Glycemic Control
The American Diabetes Association (ADA), European Diabetes Policy Group (EDPG), and American Association of Clinical Endocrinologists (AACE) have all issued recommended guidelines for glycemic control.
The ADA suggests that glycosylated hemoglobin A1C (A1C) levels should be maintained at <7.0%, which is higher than that recommended by the EDPG and AACE (6.5%).
The ADA guidelines for preprandial plasma glucose allows for a range from 90 to 130 mg/dL, but the EDPG and AACE recommend that glucose levels stay below 110 mg/dL. (For self-monitoring, EDPG recommends <100 mg/dL.) The EDPG and AACE also recommend lower postprandial glucose levels (<135 mg/dL and <140 mg/dL, respectively) compared with the ADA recommendations of <180 mg/dL.
References
American Diabetes Association. Standards of medical care in diabetes Diabetes Care. 2006;29(suppl 1):S4-S42.
Feld S. AACE Diabetes Guidelines. Endocr Pract. 2002;8(suppl 1):40-82.
European Diabetes Policy Group A desktop guide to type 2 diabetes mellitus. Diabet Med. 1999;16:
Category: Diabetes
Keywords: glycemic control, A1C, PPG, FPG, goals
*More stringent goal of <6.0% should be considered for individual patients. Generally, A1C goal for each patient is an A1C as close to normal as possible without significant hypoglycemia.
A1C = glycosylated hemoglobin A1C.
1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S European Diabetes Policy Group Diabet Med. 1999;16: Feld S. Endocr Pract. 2002;8(suppl 1):40-82.

15. Major components for patient centered care
DR.Donnell Etzwiler, founder of the IDC at Minneapolis, MN was on eof the first to develop a patient centered approach to chronic diseases.
This model reflects an approach to patient centered care in which the roles and influences of the patient, provider and the educator are recognised as the 3 major components of the health care team.
Diabetes is primarily a self managed disease, education in self management skills is essential and should be ongoing.
International Diabetes Center model of patient-centered team care

16. Staged Diabetes Management
2005, International Diabetes Center

17. Metabolic Management of type 2 DM
Nathan et al, A Consensus Statement from the American Diabetes Association and the
European Association for the Study of Diabetes. Diabetes Care,29: ,2006

18. NON-PHARMACOLOGIC MEASURES
Diabetes Self Management Training (DSMT)
Lifestyle Interventions
Ongoing Patient Education
Medical Nutrition Therapy
(MNT)
Physical Activity
SMBG
Behavioral Health
Emotional assessment
Support Needs
1. Life style intervention is very important for IGT patients (Pre-diabetes) and aggressive treatment of HTN and Dyslipidemia are also responsive to life style interventions

19. Medical Nutrition Therapy
A1c has been shown to decrease by 1% in a RCT in Type 1 Diabetics
In Type 2, a decrease in A1c of 2% in newly diagnosed cases and 1% in cases of 4 years duration
Most effective during the early stages after diagnosis of Type 2 when insulin resistance is the highest
Messages on physical activity and MNT should be the most aggressive during the early stages
Weight reduction goal is 5-10% of total body weight
Regular physical activity (approximately 150 minutes per week)

20. ‘Healthy Plate Concept’

21. Potential pathways that link Self Monitoring of Blood Glucose (SMBG)
Endocrine Practice Vol 12, Jan/Feb 2006

22. Contributions of FPG and PPG to Overall Glycemia in T2DM
290 patients not on insulin and divided into 5 gps
38 patients were investigated by CGMS
A1c is a function of both FPG and PPG- 1) Bonora et al Diabetes Care, 2001:24 2) Rohlfing et al.Diabetes Care,2002;25:
< >10.2
FPG = fasting plasma glucose. PPG: Post prandial glucose
Adapted with permission from Monnier L et al. Diabetes Care. 2003;26:

23. PHARMACOLOGIC MEASURES

24. Sites of Action of Oral Antidiabetic Agents
Liver: Glucose production
BIGUANIDES
Muscle and adipose tissue:
Peripheral glucose uptake
THIAZOLIDINEDIONES
GIT : Increase glucose
stimulated insulin
secretion
INCRETIN MIMETICS
Pancreas:
Insulin secretion
SULFONYLUREAS
MEGLITINIDES
Amylin secretion
The major metabolic defects present in type 2 diabetes mellitus that lead to glucose elevation are: decreased glucose transport and utilization at the level of muscle and adipose tissue, increased glucose production by the liver, and relatively insufficient insulin secretion by the pancreas. Added to this abnormal flux is any dietary carbohydrate that is absorbed as glucose or converted to glucose during the absorptive or postabsorptive process.
Sulfonylureas, the oldest oral agents used to treat type 2 diabetes, stimulate pancreatic insulin secretion. More recently, repaglinide, a meglitinide, has been added to the available agents that stimulate increased pancreatic insulin secretion. Insulin administration, the oldest pharmacologic therapy for diabetes is also a choice to increase circulating insulin levels in response to failing b-cell function and increased insulin resistance. Biguanides increase the sensitivity of the liver to circulating insulin, thereby reducing the level of glucose produced by the liver in type 2 diabetes.
Thiazolidinediones, peroxisome proliferator-activated receptors act at a number of sites to lower blood glucose levels. They also improve insulin sensitivity at the level of the liver, thereby decreasing the excess glucose production by that organ. They are more commonly recognized for their action in increasing peripheral insulin sensitivity in muscle and adipose tissue. By improving this sensitivity, they allow for improvement in the utilization of glucose by the muscle and adipose tissue. It should be noted that biguanides, in high doses, also have some mild effect on increasing peripheral glucose utilization.
-Glucosidase inhibitors decrease the rapid influx of carbohydrate from ingested food and slow the digestion of starches and the absorption of glucose and several other sugars.
Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens. 1998;7(5):
Intestine: Digestion and absorption of carbohydrates
a-GLUCOSIDASE
INHIBITORS a

25. Effect of Oral Therapies on A1c

26. Biguanides: inhibits hepatic glucose production, slow titration dose
Slide 3-5
Glucophage (metformin)
500 mg
850 mg
1000 mg 500 to 2550 mg daily (b.i.d.)
Glucophage XR (extended release delivery system)
500 mg
750 mg 500 to 2000 mg daily (q.d. or b.i.d.)
Inhibits hepatic glucose output by inhibiting gluconeogenesis and contributes to postabsorbtive and postprandial plasma glucose lowering effects NEJM Feb 1996 The decrease in basal hepatic glucose output co-relates with the decrease in fasting blood glucose
Also increases insulin mediated glucose disposal as demonstrated by glucose clamp procedures with muscle being the main site of action, decreases fatty acid oxidation and therefore glucose via the glucose fatty acid cycle and decreased TG due to decreased hepatic synthesis of VLDL
The peripheral actions of metformin in vitro requires high concentartions and are slow in onset

27. Metformin Dose-Response Study Mean HbA1c Reductions
Slide 3-28
Metformin Dose-Response Study Mean HbA1c Reductions
0.5
Mean Difference in HbA1c (%)
vs. Placebo at End of Study
(14 weeks)
-0.5 -1
-0.9 *
-1.2
-1.5
Metformin Dose-Response Study
The efficacy of metformin was demonstrated in this 14-week dose-response study conducted by Garber and colleagues. Metformin improved HbA1c levels when compared with placebo, with decreases ranging from -0.9% to -2.0%. The greatest benefit was achieved at the higher doses, although there was benefit even at the lowest dose studied.
In general, metformin is started at a low dose and titrated upwards to achieve target glycemic control values for HbA1c or FPG. Usually, the starting dose is 500 mg BID, increased by 500 mg per week up to a maximum of 2000 to 2500 mg per day. Gradual dose escalations may decrease the incidence of GI side effects, such as diarrhea.
(Garber, 1997) *
-1.6
-1.7 -2 * *
-2.0 *
-2.5
500 mg (n=73)
1000 mg (n=73)
1500 mg (n=76)
2000 mg (n=73)
2500 mg (n=77)
*P<0.001
Garber AJ et al., Am J Med 1997.

28. Time from randomization (y)
UKPDS Results: Obese Patients, Intensive (Metformin) vs Conventional Therapy 9 8
Median HbA1c (%) 7 6 3 6 9 12 15
Time from randomization (y)
10-year cohort
Cross-sectional
Patients followed for 10 years
All patients assigned to regimen
Conventional
Conventional
Intensive (Metformin)
Intensive (Metformin)
UKPDS Group. Lancet. 1998;352:

29. UKPDS: Effects of Intensive (Metformin) Treatment*
% Risk Reduction † ‡
ALSO HAD A 41% LOWER RISK FOR STROKE when compared with the conventional gp and risk reduction for any diabetes related end point was higher when compared to the intensive gp treated with insulin /SFU
Of the 1,704 overweight patients in the study, 342 were randomized to intensive therapy with metformin.
Patients in whom glycemic goals were not met with intensive monotherapy received combination therapy. In sulfonylurea-treated patients either metformin or insulin was added and in metformin-treated patients a sulfonylurea was added; if the glycemic goal was still not met, insulin was substituted for the sulfonylurea.
The aggregate endpoints for metformin-treated patients were:
any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in an eye, or cataract extraction)
diabetes-related mortality (death from MI, stroke, PVD, renal disease, hyperglycemia or hypoglycemia, or sudden death)
all-cause mortality.
To determine the effect of intensive treatment on vascular disease, secondary outcomes analysis included:
MI (both fatal and nonfatal and sudden death)
stroke (both fatal and nonfatal)
amputation of at least one digit or death from PVD
microvascular complications (retinopathy necessitating photocoagulation, vitreous hemorrhage, fatal and nonfatal renal failure).
Intensive metformin therapy significantly reduced any diabetes-related endpoint by 32% (P=0.0023); diabetes-related mortality by 42% (P=0.017); all-cause mortality by 36% (P=0.011); and MI by 39% (P=0.01).
The magnitude of reduction of microvascular comlications in the metformin treated gp was similar to the gp treated intensively with insulin or SFU but did not reach significance
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:
American Diabetes Association. Diabetes Care. 1999;22(suppl 1):S27-S31.
Any Diabetes- Diabetes Related Related All-Cause Endpoint Mortality Mortality MI
* Compared with conventional treatment; † P=0.0023; ‡ P=0.017; §P=0.011;
¶ P=0.01
American Diabetes Association. Diabetes Care ;22(suppl 1):S27-S31.
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:

30. UKPDS Obese Patient Cohort: Metformin and sulfonylurea/Insulin92
Weight
(kg) 87 82 1 2 3 4 5 6
Years in trial
Metformin
Sulfonylurea/insulin
United Kingdom Prospective Diabetes Study. Diabetes. 1995;44:

31. Sulphonylureas
Lower BG by increasing insulin secretion from the pancreatic beta cells
The glucose lowering effect usually plateaus at approximately one half of the maximum recommended dose *
Should be used cautiously in the elderly and those with hepatic or renal impairment
Metabolized by the liver and cleared by the kidneys
*Simonson et al.Diabetes care,1997;20:
Stenman et al. Ann.Int.Med, 1993;118:

32. Sulfonylureas (insulin secretagogues)
Slide 3-5
Sulfonylureas (insulin secretagogues)
FIRST GENERATION AGENTS- lower binding affinity to the SFU receptor and must be given in higher doses
SECOND GENERATION AGENTS
Glucotrol (glipizide) to 20 mg daily (b.i.d.)
Glucotrol XL (glipizide GITS) 2.5 to 20 mg daily (q.d.)
Micronase, DiaBeta (glyburide) to 20 mg daily (q.d.)
Glynase (micronized glyburide) 1.5 to 6 mg daily (q.d.)
Amaryl (glimepiride score tabs) 0.5 to 8 mg daily (q.d.)
Enhances insulin secretion by binding to a specific SFU receptor in the beta cells which initiates the same cascade of events as glucose does.Insulin released enters the poratl vein and the portal hyperinsulinemia suppresses the HGP Large prospective placebo controlled trials have shown that glipizide,glyburide and glimepiride exert equipotent glucose lowering effects
Short term studies have shown that glipizide releases insulin more rapidly than glyburid
GITS-gastrointestinal therapeutic system which allows a slow release over 24 hrsTitrate up every 1-2 weeks to get the desired FBG
75% of the hypoglycemic action of the SFU is usually observed with a daily dose that represents half of the maximally effective dose and it is unlikely that further dose increase will have a clinically significant effect on blood glucose level

33. Thiazolidinediones
Pharmacological ligands for a nuclear receptor known as the PPAR 
When activated, this receptor binds to response elements on DNA and alters transcription in various genes to regulate carbohydrate and lipid metabolism
Through this process increase insulin stimulated glucose uptake in the skeletal muscle cells

34. Molecular Targets of PPAR & PPAR action
NEJM 2004; 351:

35. Thiazolidinediones
Indicated as monotherapy and in combination with SFU, metformin & insulin
Weight gain & edema are commonly seen when used with insulin
Contraindicated in patients with CHF and hepatic impairment
Additionally combining 2 sensitizers produces and additive effect*
*Einhorn et al.Clin.Ther.2000;22:

36. Glinides (Nateglinide and Repaglinide)
Rapid but short lived release of insulin that lasts 1 to 2 hours
Attenuate post prandial glucose excursions, therefore should be used to target PP blood glucose levels
Repaglinide (Prandin) is more potent ,is minimally cleared by the kidneys and can be used safely with severe renal impairment

37. Nateglinide: Meal-Related Insulin Levels in type 2 diabetes
120
(n = 10) After 1 Wk Tx
NAT 120 mg ac x 3*
Placebo ac x 3
100 80
Insulin (µU/mL) 60 40
Rapid but brief release of insulin 20
Meal
Meal
Snack
Meal
Time (hours post-morning dose)
*No dose taken with snack. Walter YH, et al. Eur J Clin Pharm. 2000;56:129–133.

38. -Glucosidase Inhibitors delays digestion of carbohydrates and slows glucose absorption, slow titration dose
Slide 3-5
Precose (acarbose)
25 mg
50 mg
100 mg 75 to 300 mg daily (t.i.d.) before meals
Glyset (miglitol)
No significant advantage over Acrabose
Inhibits the ability of enzymes in the small intestine brush border to break oligo and disccharides to monosaccharides and by delaying there absorbtion shifts their absorption to more distal parts of the intestine and colon and therefore retards glucose entry into the systemic circulation

39. -Glucosidase Inhibitors
Advantage Disadvantage
Require high-carbohydrate diet
Must be taken before every meal
Modest efficacy
Flatulence and GI side effects
Elevated LFT’s have been reported
Long history of use
Good safety profile
No weight gain
Mild stool softening
No substantial systemic drug-drug interaction
Good adjunctive therapy
Primarily effects PP BG
Most useful in patients with new onset type 2 who have mild fasting hyperglycemia and in patients on Metformin or SFU and also in those with predominant postprandial hyperglycemia
Lebovitz HE, Diabetes Reviews 1998.

40. INCRETINS GLP 1 – Glucagon like peptide 1
GIP – Glucose dependant insulinotropic polypeptide

41. GLP-1 GIP Is released from L cells in ileum and colon1,2
Is released from K cells in duodenum1,2
Stimulates insulin response from beta cells in a glucose-dependent manner1
Inhibits gastric emptying1,2
Has minimal effects on gastric emptying2
Reduces food intake and body weight2
Has no significant effects on satiety or body weight2
Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1
Does not appear to inhibit glucagon secretion from alpha cells1,2
GLP-1 and GIP Are Incretin Hormones
GLP-1 and GIP are the currently identified incretin hormones.
An incretin is a hormone with the following characteristics1:
It is released from the intestine in response to ingestion of food, particularly glucose.
The circulating concentration of the hormone must be sufficiently high to stimulate the release of insulin.
The release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (glucose-dependent).
GIP and GLP-1 are hormones that fulfill these 3 characteristics, qualifying them as incretins.1
In the fasting state, GIP and GLP-1 circulate at very low levels. Their levels rapidly increase after food ingestion and play a role in the release of insulin.2,3
GLP-1 stimulates insulin response from beta cells in a glucose-dependent manner and suppresses glucagon secretion from alpha cells in a glucose-dependent manner. GIP also potentiates insulin release from beta cells in a glucose-dependent manner.4 Other effects of GLP-1 and GIP are summarized on the slide.
1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.
2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
References:
1. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
2. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.
3. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287:E199–E206.
4. Meier JJ, Nauck MA. Glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606.

42. Modulation of Insulin and Glucagon Levels: The Enteroinsular Axis
Nutrient signals
Hormonal signals
GLP-1
GIP
Neural signals
Insulin
(GLP-1,GIP)
Glucagon
(GLP-1)
alpha cells
beta cells
Pancreas
Modulation of Insulin and Glucagon Levels: The Enteroinsular Axis
A close association exists between the gut and the pancreatic islets, a relationship that has been called the “enteroinsular, or incretin, axis”.1 This axis encompasses different types of signals between the gut and the pancreas, including hormonal signals, neural signals, and nutrient signals.1 The hormonal signals in the enteroinsular axis are the incretins.1
Incretins affect the activity of insulin-secreting beta cells, causing a lowering of plasma glucose levels by modulation of insulin release.2 Importantly, the glucose-lowering effect of incretin hormones is glucose-dependent:
Both GLP-13 and GIP4 have only minimal activity on insulin secretion at fasting or basal glucose levels.
In addition to its incretin effect, GLP-1 has a modulating effect on the glucagon-secreting pancreatic alpha cells.5 This effect is glucose-dependent as well.6
A relationship exists between nutrient-induced release of GI factors and pancreatic function. Incretins released from the gut in response to nutrient intake partly modulate insulin secretion, and GLP-1 also modulates glucagon secretion.
Gut
Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag.
Drucker DJ. Diabetes Care. 2003;26:2929–2940.
Kieffer T et al. Endocr Rev. 1999;20:876–913.
Nauck MA et al. Diabetologia. 1993;36:741–744.
References:
1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. D’Alessio DA, Vahl TP. Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004;286:E882–E890.
4. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

43. The Incretin Effect in Subjects Without and With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1 80 60 40 20 80 60 40 20
The incretin effect is diminished
in type 2 diabetes.
Incretin Effect
nmol / L
nmol/L
IR Insulin, mU/L
IR Insulin, mU/L
The Incretin Effect in Subjects Without and With Type 2 Diabetes
In 1964, it was demonstrated that the insulin secretory response was greater when glucose was administered orally through the GI tract than when glucose was delivered via intravenous (IV) infusion. The term incretin effect was coined to describe this response involving the stimulatory effect of gut hormones known as incretins on pancreatic secretion.1,2
The incretin effect implies that nutrient ingestion causes the gut to release substances that enhance insulin secretion beyond the release caused by the rise in glucose secondary to absorption of digested nutrients.1
Studies in humans and animals have shown that the incretin hormones GLP-1 and GIP account for almost all of the incretin effect,3 stimulating insulin release when glucose levels are elevated.4,5
Although the incretin effect is detectable in both healthy subjects and those with diabetes, it is abnormal in those with diabetes, as demonstrated by the study shown on the slide.6
In this study, patients with type 2 diabetes and weight-matched metabolically healthy control subjects were given glucose either orally or IV to achieve an isoglycemic load.6
In those without diabetes (shown on the left), the plasma insulin response to an oral glucose load was far greater than the plasma insulin response to an IV glucose load (incretin effect)—that is, the pancreatic beta cells secreted much more insulin when the glucose load was administered through the GI tract.6
In patients with type 2 diabetes (shown on the right), the same effect was observed but was diminished in magnitude.6
The diminished incretin effect observed in patients with type 2 diabetes may be due to reduced responsiveness of pancreatic beta cells to GLP-1 and GIP or to impaired secretion of the relevant incretin hormone.7,8 60
120
180 60
120
180
Time, min
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
References:
1. Creutzfeldt W. The incretin concept today. Diabetologia. 1979;16:75–85.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology. 2004;145:2653–2659.
4. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46–52.
7. Creutzfeldt W. The entero-insular axis in type 2 diabetes—incretins as therapeutic agents. Exp Clin Endocrinol Diabetes. 2001;109(suppl 2):S288–S303.
8. Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307.

44. GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
Meal
Intestinal GIP and GLP-1 release
DPP- 4
Enzyme
GIP-(1–42)
GLP-1(7–36)
Intact
GIP-(3–42)
GLP-1(9–36)
Metabolites
GLP-1 and GIP Are Degraded by the DPP-4 Enzyme
GLP-1 and GIP have short biological half-lives; they are rapidly degraded by DPP-4.1–3
DPP-4 is a widely expressed enzyme present on cells in many tissues, including the kidney, GI tract, biliary tract and liver, placenta, uterus, prostate, skin, lymphocytes, and endothelial cells (which may be involved in the inactivation of circulating peptides).4
Rapid Inactivation
Half-life*
GLP-1 ~ 2 minutes
GIP ~ 5 minutes
GIP and GLP-1 Actions
Deacon CF et al. Diabetes. 1995;44:1126–1131.
*Meier JJ et al. Diabetes. 2004;53:654–662.
References:
1. Deacon CF, Nauck MA, Toft-Nielsen M, Pridal L, Willms B, Holst JJ. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44:1126–1131.
2. Kieffer TJ, McIntosh CHS, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology ;136:3585–3596.
3. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80:952–957.
4. Drucker DJ. Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs. 2003;12:87–100.

45. Effective GLP 1 therapies:
Exenatide (Byetta)– binds to and activates the GLP 1 receptor and resists degradation by DPP-4 (April 2005)
Sitagliptin (Januvia) – resistant to DPP-4 degradation (October 2006)
Vildagliptin – inhibits the DPP-4 enzyme (Under review by FDA)
Byetta approved in April 2005
Januvia approved in October 2006

46. Byetta (Exenatide) patients withType 2 DM who are taking
Indicated as an adjunctive therapy in
patients withType 2 DM who are taking
Metformin, SFU or a combination and TZD
but has not achieved adequate control
Not recommended for use in patients
with ESRD, severe renal impairment, or
severe gastrointestinal disease and in
Type 1 Diabetics

47. Byetta (Exenatide) Major side effect is nausea.
Recent FDA warning of acute pancreatitis being associated with Byetta.
Prescribed as a subcutaneous injection given within 1 hour before the morning and evening meal
Starting dose is 5 ug BID and can be increased to 10 ug BID

48. Exenatide versus Insulin Glargine
26 week multicenter,open label
randomized,controlled trial
551 patients with type 2 DM
and inadequate glycemic control
Exanetide 10 ug twice daily or
Insulin glargine daily to maintain
a fasting BG of <100mg added to
The patients current regimen
Heine et al. Ann Int Med.October 2005;143:

49. Heine et al. Ann Int Med.October 2005;143:559-569
Weight loss is early as 2 weeks
Heine et al. Ann Int Med.October 2005;143:

50. 30 weeks placebo controlled
with patients receiving
Metformin 1500mg with
Byetta.
Open label extension of the
Byetta/Metformin arm for an
additional 52 weeks

51. Sitagliptin (Januvia) DDP-4 inhibitor
Monotherapy or in combination with Metformin, TZD, Glimepiride ± Metformin
Mainly target PPG but have been shown to decrease FBG levels
Daily recommended dose is 100mg orally once a day
Dose adjustment is required in moderate to severe renal insufficiency

53. “Although insulin therapy has not traditionally been implemented early in the course of Type 2 diabetes, there is no reason why it should not be…”
Key Words:
Insulin
Type 2
Nathan DM. NEJM. Oct 24, 2002;347(17):

54. Physiologic Blood Insulin Secretion Profile75
Breakfast
Lunch
Dinner 50
Plasma Insulin (µU/mL) 25
Physiologic Blood Insulin Secretion Profile
Physiologic insulin secretion has two components: basal insulin + bolus insulin to cover PPG excursions. Basal or bolus insulin alone is not physiologic therapy.
There is a basal level of insulin secretion, and then a surge of insulin secretion (bolus) to cover mealtime needs. This is what occurs in people without diabetes.
Ideally, every patient with diabetes would be managed with a therapy that would mimic the normal physiologic profile as closely as possible. This typically requires what we call “intensive insulin therapy” or MDI (multiple daily injections).
The goals are to:
Maintain near-normal glycemia
Minimize long-term complications, both microvascular and macrovascular
Improve quality of life
Key words:
Physiologic
Insulin profile
White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

55. Loss of Early Insulin Release Leads to Postprandial Hyperglycemia
Plasma Insulin
Plasma Glucose 60
360
270 40
(mg/dL)
(mU/L)
180 20 90
Loss of Early Insulin Release Leads to Postprandial Hyperglycemia
Mitrakou and colleagues conducted a study to assess the contribution of the liver, muscle and diminished splanchnic glucose uptake to postprandial hyperglycemia in 10 patients with Type 2 diabetes following a 1 gm/kg oral glucose tolerance test (OGTT) (maximum 75 gm dose).
The first graph presents insulin levels and the second graph shows glucose levels. As insulin level is lower in patients with diabetes it explains high glucose levels.
The graphs on this slide show that patients with diabetes have a blunted and delayed response to insulin with higher and prolonged glucose excursions compared with nondiabetic subjects.
In addition, in contrast to normal subjects, there was an initial rise, rather than fall, in postprandial glucagon (data not shown).
The authors concluded that impaired suppression of endogenous hepatic glucose production was the primary cause of postprandial hyperglycemia.
Mitrakou A, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39:1381–1390. –1 1 2 3 4 5 –1 1 2 3 4 5
Hours After Glucose Ingestion
Healthy Subjects
Patients With Type 2 Diabetes
Mitrakou A, et al. Diabetes. 1990;39:1381–1390.

56. INSULINS Peak (duration) hrs
RAPID-ACTING INSULIN ANALOGS
Humalog (lispro) (2-6)
Novolog (aspart) (2-6)
Glulisine (epidra) (2-6)
SHORT-ACTING
- Regular (3-6)
INTERMEDIATE-ACTING
NPH (10-24)
LONG ACTING
Lantus / glargine none (10-24)
Levemir / detemir
Insulin detemir has a slight peak and is used BID
Genetically engineered new insulins by changing the order of amino acids that make up human insulin, absorbed faster and quicker onset of action
LANTUS forms microprecipitates after being injected S/Q

57. Fixed dose insulin mixes
HUMULIN (NPH/REG)
70/30
50/50
HUMALOG (Prot-lispro/free lispro)
75/25
NOVOLIN (NPH/REG)
NOVOLOG MIX (Prot-aspart/aspart)

58. Insulin delivery devices

60. Ideal Basal/Bolus Insulin – elementary principal
Slide 3-23
Ideal Basal/Bolus Insulin – elementary principal 75 50 25
Breakfast
Lunch
Dinner
Glucose
Bolus Insulin
Base Insulin
Plasma
Insulin
(U/mL)
Ideal Basal/Bolus Insulin Absorption Pattern
Ideally, what is needed is:
A short-acting insulin with immediate onset and a shorter duration of action; and
A long-acting insulin that provides consistent insulin availability—sufficient to prevent interruptions in basal insulin levels.
Currently these two preparations are in development (short-acting insulin aspart and long-acting insulin glargine), and it is anticipated that they will be available in 2000.
4:00
8:00
12:00
16:00
20:00
24:00
4:00
8:00
Time
Skyler J, Kelley’s Textbook of Internal Medicine 2000.

61. OPTIONS………
Once daily background or basal insulin if fasting BG is elevated but glucose values remain stable during the day,
Once daily or twice daily pre-mixed insulin analogue, orally administered drugs may or may not be continued
Basal bolus therapy…..first initiate basal along with 1 bolus injection before the largest meal and eventually at each meal ,if needed

62. What doses to start with……..
With HbA1c <8%, begin 0.1U/Kg body weight
HbA1c 8-10%, start 0.2U/kg body weight
HbA1c >10%, start 0.3U/Kg body weight
With pre-mixes can divide the total dose by 2 if used twice a day
With insulin glargine, adjust dose every 3-7 days until target fasting dose is reached
Bergenstal Endocrine Practice,Jan 2006

63. Advantages of rapid acting insulin analogs
Restores the early insulin peak in combination with meal ingestion
Prevents the hyperinsulinemia resulting from the late absorption of regular insulin and thereby protects against hypoglycemia

64. Human Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Change in serum insulin
Theoretical representation of expected insulin release in nondiabetic subjects
Baseline
Level
Human Insulin Time-Action Patterns
Key Words:
Insulin profile
Time (hours)
SC injection

65. Human Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Regular insulin (human)
Change in serum insulin
Theoretical representation of profile associated with Regular Insulin (human)
Baseline
Level
Human Insulin Time-Action Patterns
Characteristics of regular insulin (mealtime)
Should inject 30 minutes before meals
Risk of early postprandial hyperglycemia
Risk of late postprandial hypoglycemia
Key words:
Insulin profile
Regular Human Insulin
Time (hours)
SC injection

66. Analog Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Change in serum insulin
Theoretical representation of expected insulin release in nondiabetic subjects
Baseline
Level
Analog Insulin Time-Action Patterns
Key words:
Insulin profiles
Time (hours)
SC injection

67. Analog Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Rapid-Acting Insulin Analog
Change in serum insulin
Theoretical representation of profile associated with rapid-acting Insulin Analog
Baseline
Level
Analog Insulin Time-Action Patterns
Key words:
Insulin profiles
Time (hours)
SC injection

68. Human Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
NPH insulin (human)
Change in serum insulin
Theoretical representation of profile associated with NPH Insulin
Baseline
Level
Human Insulin Time-Action Patterns
Characteristics of NPH insulin (basal)
No control of early hyperglycemia
Increased risk of late hypoglycemia
Key words:
Insulin profile
NPH
Time (hours)
SC injection

69. Human Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Human Premix 70/30
(70% NPH & 30% Regular)
Theoretical representation of profile associated with Human Premix 70/30
Change in serum insulin
Baseline
Level
Human Insulin Time-Action Patterns
Characteristics of Human Premix 70/30 are the same as NPH and Regular Human Insulin because it contains 70% NPH and 30% Regular Human Insulin. Because it is a mix of these 2 insulins, there is an additive effect which creates a broader peak.
Characteristics of NPH insulin (basal)
No control of early hyperglycemia
Increased risk of late hypoglycemia
Characteristics of regular insulin (mealtime)
Should inject 30 minutes before meals
Risk of early postprandial hyperglycemia
Risk of late postprandial hypoglycemia
Key words:
Insulin profile
Human Premix 70/30
Regular Human Insulin
NPH
Human
Time (hours)
SC injection

70. Analog Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
QD (basal) Analog Insulin
Change in serum insulin
Theoretical representation of profile associated with Basal Analog Insulin
Baseline
Level
Analog Insulin Time-Action Patterns
QD (basal) analog insulin alone provides
limited coverage against early hyperglycemia Basal analog insulin alone does not cover postprandial glucose excursions
Key Words:
Insulin profile
Basal Analog
Time (hours)
SC injection

71. Analog Insulin Time-Action Patterns
Normal insulin secretion
at mealtime
Insulin Analog Premix
Change in serum insulin
Theoretical representation of profile associated with Insulin Analog Premix
Baseline
Level
Analog Insulin Time-Action Patterns
Key words:
Insulin profiles
Time (hours)
SC injection

72. USE COMBINATION THERAPY
AND
GET PATIENTS TO GOAL
AS SOON AS POSSIBLE

73. Significant Loss of Beta­Cell Function at Diagnosis
UKPDS
At the time diabetes was diagnosed, 50% of beta­cell function was lost
Beta­cell function continued to decline over the 10-year course of the study
Correlated with loss of response to oral therapy
Secondary failure (progressive loss of beta cell)
Significant Loss of Beta-Cell Function at Diagnosis
Each therapeutic agent, as monotherapy, increased 2- to 3-fold the proportion of patients who attained A1C below 7% compared with diet alone. However, the progressive deterioration of diabetes control was such that after 3 years only 50% of patients could attain this goal with monotherapy, and by 9 years this declined to approximately 25%. The majority of patients need combination therapy or insulin to attain these glycemic target levels in the longer term.
Key words:
Type 2
Beta cell
Dysfunction
UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UKPDS. Diabetes. 1995;44:
Turner RC, et al. Glycemic control with diet, sulfonylurea, metfornin, or insulin in patients with type 2 diabetes: progressive requirement for multiple therapies (UKPDS 49). UKPDS. JAMA Jun 2;281(21):
UKPDS 16. Diabetes. 1995;44:
Turner RC, et al. JAMA Jun 2;281(21):

74. Progression of Type 2 DM UKPDS Diabetes1995;44:1249-1258
Decline in beta cell function. Dashed line shows extrapolation forward and backward from yours 0-6 based on the HOMA model
Findings from the UKPDS have shown us that affected individuals have already lost 50 \% of beta cell function at the time of type 2 DM is diagnosed and there is a progressive decline in pancreatic insulin secretion
UKPDS Diabetes1995;44:

75. Progression of Type 2 DM FPG HbA1c UKPDS. Lancet 1998;352:854-65
After an initial and similar decrease in HbA1c with metformin, SFU and insulin,the rate of increase in the HbA1c value was similar to the gp treated with diet therapy
Combination therapy early in the disease will make the most difference in terms of HbA1c treatment targets and increased dosages of a single drug is not the right treatment strategy for a progressive disease
Time from randomization in years
Time from randomization in years
UKPDS. Lancet 1998;352:854-65

76. HbA1c: Conventional vs Intensive Treatment in Major Clinical Trials
DCCT
Kumamoto Study 10 9 8 7 6 5 12 11 10 9 8 7 6 5
HbA1c (%)
HbA1c (%)
Years
Months
UKPDS 9 8 7 6
In the DCCT, Kumamoto Study, and UKPDS, HbA1c (shown on the y axis) was significantly reduced for up to 15 years in patients treated with intensive diabetes therapy (in red) compared to those treated with conventional diabetes therapy (in yellow).
Conventional therapy
Intensive therapy
HbA1c (%)
DCCT Study Group: N Engl J Med 329:977-86, 1993
Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995
Years
UKPDS Study Group: Lancet 352:837-53, 1998

78. COMBINATION THERAPY
AACE Guidelines, Endocrine Practice, May/June 2007

79. Finally, Type 2 DM is a progressive disease with worsening glycemia over time.
Therefore, addition of medications is the rule, not the exception, if treatment goals are to be met over time.