1. Glucose Homeostasis
The body must control glucose levels because all cells use glucose to make ATP, the energy currency of cells. Some tissues like brain almost never burn any other fuel molecule. But too much glucose damages cells by getting attached to certain proteins and changing their function. Key tissues in this balancing act are:
Liver
Fat
Muscle
Brain
Pancreas (endocrine cells)

2. Diabetes mellitus
The incidence of diabetes mellitus is growing rapidly, it estimated that 135 million people are affected.
Diabetes is characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin.
Can be divided into 2 groups based in required to insulin:
(1) Insulin dependent diabetes (type 1)
(2) non-Insulin dependent diabetes (type 2)
Gestational diabetes is another type and defined as a glucose intolerance associated with pregnancy.

3. Diabetes mellitus
Type 1 most common around the age of puberty but can occur at any age.
Type 2 is influenced by genetic factor, obesity, aging, and peripheral insulin resistance.
treatment here is to maintain blood glucose concentration within normal limits and to prevent the development of long-term complication.
weight loss, exercise, and dietary modification decrease insulin resistance and correct hypoglycemia in some patient. However most are dependent on pharmacological intervention with oral hypoglycemic agents.

4. TYPES OF INSULIN PREPARATIONS
1. Ultra-short-acting
2. Short-acting (Regular)
3. Intermediate-acting
4. Long-acting

5. Short-acting (regular) insulins
e.g. Humulin R, Novolin R
Uses
Designed to control postprandial hyperglycemia & to treat emergency diabetic ketoacidosis
Physical characteristics
Clear solution at neutral pH
Chemical structure
Hexameric analogue
Route & time of administration
S.C. 30 – 45 min before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
Onset of action
30 – 45 min ( S.C )
Peak serum levels
2 – 4 hr
Duration of action
6 – 8 hr
Usual administration
2 – 3 times/day or more
Ultra-Short acting insulins
e.g. Lispro, aspart, glulisine
Similar to regular insulin but designed to overcome the limitations of regular insulin
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15 min) before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)
0 – 15 min ( S.C )
30 – 90 min
3 – 4 hr
2 – 3 times / day or more

6. 3. Intermediate - acting insulins
e.g. isophane (NPH)
Turbid suspension
Injected S.C.(Only)
Onset of action hr
Peak serum level hr
Duration of action hr
Insulin mixtures
75/ /30 50/50 ( NPH / Regular )

7. 4. Long – acting insulins e.g.Insulin glargine Onset of action 2 hr
Absorbed less rapidly than NPH&Lente insulins.
Duration of action upto 24 hr
Designed to overcome the deficiencies of intermediate acting insulins
Advantages over intermediate-acting insulins:
Constant circulating insulin over 24hr with no pronounced peak.
More safe than NPH& Lente insulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).
Clear solution that does not require resuspention before administration.

8. Insulin Types Rapid-acting - Humalog ®, Novolog ®, Apidra
Short-acting - Regular
Intermediate - NPH
Long-acting - Glargine (Lantus), Detemir (Levemir)
The graph on this slide represents the action patterns of insulin types in use today.
Intermediate- and long-acting insulins provide basal insulin concentrations and doses are adjusted based on the student’s pattern of blood glucose. They are not used for acute treatment of high blood glucose levels and are not generally given before meals eaten at school. Intermediate and long-acting insulins are referred to as basal insulin. Basal insulin controls the blood glucose in the fasting state, when you’re not eating. Basal insulin is typically 50% or less of an individual’s total daily insulin dose.
Rapid-acting insulins act quickly within minutes and are used primarily to treat a high blood sugar level and to “match” or “cover” a rise in blood glucose levels following food intake. Many students require rapid acting insulin before meals and snacks. Note, hypoglycemia can occur if meal or snack is delayed for than 15 minutes after injection of rapid-acting insulin. Rapid-acting insulin is frequently referred to as bolus insulin. Rapid-acting insulin is also used in insulin pumps.
Short-acting insulins are used like rapid-acting insulins, but have a longer duration of action and a delayed peak. Short-acting insulin is also referred to as bolus insulin.

11. Western regimen             
Multiple Insulin Injection Therapy I N S U L J E C T O
 
Two doses:
The usual dosing commonly used.
Initial insulin therapy
  
Three doses:
Used for active patients.
Patients taking two main meals.
   
Four doses:
Brittle diabetic patient.
Pregnant mothers specially type 1.
   
Four doses:
Brittle diabetic patient.
Pregnant mothers specially type 1.
Motivated patients.

12. Western regimen             
Multiple Insulin Injection Therapy I N S U L J E C T O
 
Two doses:
The usual dosing commonly used.
Initial insulin therapy
  
Three doses:
Used for active patients.
Patients taking two main meals.
   
Four doses:
Brittle diabetic patient.
Pregnant mothers specially type 1.
   
Four doses:
Brittle diabetic patient.
Pregnant mothers specially type 1.
Motivated patients.

13. Dosing Insulin
Generally, patient will only take rapid or short acting insulin at meal or snack times:
1:10 ratio; 1 unit of insulin for every grams of carb eaten
Calculate: Meal of 60 grams CHO
60/10 = 6
6 unite of insulin are needed to cover this meal

14. Correction Bolus to Lower Blood Glucose
Amount to lower blood glucose to target, usually calculated by sliding scale or correction factor:
Sliding scale: give units of insulin for each interval of BG
Example: 1 unit , 2 units , 3 units 250+
Correction factor: Blood glucose level – target blood glucose/correction factor = units insulin to be given
Example: BG=150 (actual) minus Target BG (100) = 50 divided by Correction factor (50) = 1 unit insulin needed

15. Insulin
In hyperglycemic emergency, regular insulin (unmodified) in injected intravenously.
Adverse effects of insulin:
the symptoms of hypoglycemia is the most serious and common to overdose of insulin.
Weight gain
other adverse effects include lipodystrophy, a lump or small dent in the skin that forms when a person keeps performing injections in the same spot). (less common with human insulin), and allergic reaction.
diabetics with renal insufficiency must have their doses of insulin adjusted.

16. Oral hypoglycemic agents
Are useful in treatment of type 2 diabetes patient that cannot manage their glucose level by diet only.
Patients with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia.
The insulin is added because of the progressive decline in beta-cells that occur due to the disease or aging.
Oral hypoglycemic agents should not be given to patients with type 1 diabetes.

18. Sulfonylureas (Oral Hypoglycemic drugs)
First generation
Second generation
Short
acting
Long
acting
Short
acting
Intermediate
acting
Long
acting
Glyburide
(Glibenclamide)
Glimepiride
Tolbutamide
Acetohexamide
Tolazamide
Chlorpropamide
Glipizide

19. Sulfonylureas Glimepiride (Amaryl) 1, 2, 4 mg tablets Glipizide
(Glucotrol, Glucotrol XL)
(2.5), 5, 10 mg (XL)
Glyburide
(DiaBeta)
1.25, 2.5, 5 mg
Indications
Adjuncts to diet and exercise to lower blood glucose in patients w/ type II diabetes mellitus
MOA
Stimulating insulin release from beta-cells of pancreatic islets

20. Sulfonylureas
These agents bind to an ATP-dependent K+ channel on the cell membrane of pancreatic beta cells.
this binding promote insulin secretion from beta-cells of the pancreas, resulting in a reduction in the glucose serum level
Their adverse effects include weight gain, hyperinsulinemea, and hypoglycemia.
They are contraindicated in patient with hepatic and renal insufficiency.

21. Drugs other than Sulfonylurea
Meglitinides
Biguanides
α-Glucosidase
Inhibitors
Thiazolidinediones
Repaglinide
Nateglinide
Metformin
Acarbose
Rosiglitazone
Pioglitazone

22. Metformin
Metformine increase the glucose uptake and utilization by the target tissues, thereby decreasing insulin resistance.
Like Sulfonylureas, Metformin requires insulin for its action, but differ from Sulfonylureas in that it does not promote insulin secretion. (The risk of hypoglycemia is far less than Sulfonylureas agents).
Metformin reduce hepatic output largely by inhibiting gluconeogenesis. It also slows intestinal absorption of sugars.
Importantly, Metformin has a property of modestly reduce the hyperlipidemia and is the only hypoglycemic agent proven to decrease cardiovascular mortality.

23. Metformin
Metformin is the drug of choice in newly diagnosed type 2 diabetes.
The side effect are largely gastrointestinal. Metallic taste in the mouth
Contraindicated in patient with hepatic and renal diseases, cardiac or respiratory insufficiency, severe infections, and pregnancy.
Long term use may interfere with vitamin B12 absorption.
Lactic acidosis ( rare – 01/ 30,000-exclusive in renal & hepatic failure)

24. Advantages of Metformin over SUs
Does not cause hypoglycemia
Does not result in wt gain
( Ideal for obese pts )

25. Glitazones
Although insulin is required for its action, they do not promote its release from the beta-cells. Thus, hyperinsulinemia does not result.
They act by binding to a group of receptor molecules inside the cell nucleus, resulting in a decrease in the insulin resistance.
This group has two members: Pioglitazone, and Rosiglitazone.
Resiglitazone can be used in combination with other hypoglycemic agents but not with insulin, because edema occur with higher frequency.

26. Glitazones
The main side effect is fluid retention, leading to edema, weight gain, and potentially aggravating heart failure. Therefore, contraindicated in patients with decreased ventricular function.
Because an old member of this group (Troglitazone) was withdrawn from the market due to an increased incidence of drug-induced hepatitis. It is now common practice that liver enzymes are monitored during the first year of treatment with the newer Glitazones.

27. Special Alert February 2011
Addition of Risk Evaluation and Mitigation Strategy to rosiglitazone. The medication is restricted to those patients already on rosiglitazone, for fails pioglitazone or cannot be managed by other oral antidiabetic medications.

28. Alpha-Glucosdase inhibitors
Acarbase and Miglitol, are the members. they are taken in the beginning of the meals.
Act by delayed the digestion of carbohydrates, thereby decreasing the glucose absorption.
Both agents exert their effect by reversibly inhibiting membrane-bound alpha-Glucosdase in the intestine brush boarder.
These agents have No effect on insulin release or action on the targeted tissue, and so do not produce hypoglycemia.

29. Alpha-Glucosdase inhibitors
The major side effect is flatulence, diarrhea, and abdominal cramps
Patient with inflammation bowel disorder, colonic ulceration, and intestinal obstruction should not use them (contraindicated).

30. GLP-1 localisation
Cleaved from proglucagon in intestinal L-cells (and neurons in hindbrain/hypothalamus)
Secreted in response to meal ingestion
Cleared via the kidneys

31. GLP-1 Modes of Action in Humans
Upon ingestion of food…
Stimulates glucose-dependent insulin secretion
Suppresses glucagon secretion
DISCUSSION POINTS:
Upon ingestion of meals containing carbohydrates and fats, GLP-1 is secreted from the L-cells in the intestine. This secretion of GLP-1 sets off a collection of actions which work in concert to help regulate glucose homeostasis:
Glucose dependent enhancement of insulin secretion
Suppression of inappropriately high glucagon secretion
Slowing of gastric emptying
Exogenous GLP-1 reduced food intake, and improved insulin sensitivity, in both animal studies and a 6-week study in patients with type 2 diabetes.
In animal studies, exogenous GLP-1 increased beta-cell mass through beta-cell proliferation and neogenesis.
SLIDE BACKGROUND:
[This is an animated slide]
Slows gastric emptying
GLP-1 is secreted
from the L-cells
in the intestine
Reduces food intake
This in turn…
Increases beta-cell mass and maintains beta-cell efficiency

32. Dipeptyl- peptidase inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
Septagliptin
Allogliptin

33. Sitagliptin Has a Weight Neutral Profile
Monotherapy studies
No increase in body weight from baseline with sitagliptin compared with a small decrease in the placebo group
Add-on to metformin
A similar decrease in body weight for both treatment groups
Add-on to pioglitazone
No significant difference in body weight between treatment groups
Noninferiority vs Sulfonylurea
A significant reduction in body weight with sitagliptin versus weight gain with glipizide
Sitagliptin Has a Generally Weight Neutral Profile
Body weight did not increase from baseline with sitagliptin in either the 18-week or 24-week monotherapy study, compared with a small reduction in the body weight of patients given placebo.1,2
A slight but similar decrease in body weight of patients was observed in both treatment groups of the add-on study with metformin.2
There was no significant difference between sitagliptin and placebo in body weight change in the add-on study with pioglitazone.3
Overall, sitagliptin appeared to have a neutral effect on body weight.4
Purpose:
To review the body weight profile for sitagliptin.
Take-away:
Sitagliptin has a generally weight neutral profile. 46
Reference
1. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman, DE, for the Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637.
2. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637.
3. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein, P, for the Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–1568.
4. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.

34. Comparing the Gliptins
Sitagliptin Vildagliptin Saxagliptin
Dosing OD BD OD
Renal Failure Approved Not Approved Approved
Hepatic Failure No info No info Safe
With Insulin Not Approved Approved Studies Pending
On Bone Improved BMD? Unknown Unknown
Infections Slight increase Neutral Neutral
UTI, URI
Cardiac Impact Reduced Neutral ?reduced CV mortality
post ischaemic stunning