1. Clinical Diabetes basic training
Eden Miller D.O.

2. Global Prevalence of Diabetes Projected to More Than Double by 2030
Europe:
2000: 33 million
2030: 48 million
Africa and Middle East 2000: 22 million 2030: 61 million
Asia and Australia
2000: 83 million
2030: 190 million
The Americas
2000: 33 million
2030: 67 million
The projections illustrated in this slide, based on World Health Organization data, are for the year 2030, when diabetes is predicted to affect some 366 million people worldwide, or more than twice as many as in 1995, when 135 million patients had (documented) diabetes.1-3 [1/8; 2/1047/Abstract; 3/1416/1/3]
Although the prevalence of diabetes is expected to increase worldwide, the countries with the greatest numbers of people with diabetes are now—and will be in the year 2030—India, China, and the US.3 [3/8]
1WHO. Diabetes Action Now
2Wild S, et al. Diabetes Care. 2004:27:
3King H, et al. Diabetes Care. 1998;21:
World
2000: 171 million
2030: 366 million
<2% %-5% 5%-8% 8%-11% 11%-14%
Nationwide Diabetes Prevalence Categories
WHO. Diabetes Action Now

3. What is diabetes?
An impairment of the body’s ability to effectively transport glucose into the cell so it may be utilized for fuel. Insulin, the body hormone responsible for the transport of glucose, is either less potent, decreased, or absent in a diabetic individual.

5. A touch of Sugar (fasting serum)
Glucose intolerance: 1O5-113
Pre diabetes:
Diabetes: 126 or greater

6. Hemoglobin A1C, its just an average
What is it- the measured percentage of glucose attached to a red cell. It is a representative of the average blood sugars over a 2-3 month period. Why 3 months- the body replaces the blood volume every 3 months. Why measure- it may assist in the diagnosis of diabetes. Typically used to monitor overall diabetes control. Often a measure used in research.

7. A1C what should it be? A.D.A.- less than 7% A.C.E.- less than 6.5%
What does that percentage mean in terms of numbers. 6% % %-205
9% % % %-345

8. A1C Goals: Aim for the Lowest A1C Possible
Presenter reviews ADA and ACE targets

9. Glucose Fluctuations Are Not Adequately Measured by A1C
Mean A1C = 6.7%
400
300
Optional
DISCUSSION POINTS:
Excessive glucose fluctuations are common in diabetes and are not measured by the A1C.
People without diabetes are able to maintain their glucose concentrations within a narrow band (approximately 80 to 140 mg/dL) throughout the day.
For patients with diabetes, this level of glucose control is difficult. Even “optimally-treated” patients, whose A1C would predict near target glucose control, can experience wide glucose fluctuations throughout the day.
In a recent study, Amylin Pharmaceuticals, Inc. assessed 24-h glucose profiles of 9 subjects with type 1 diabetes whose A1C averaged 6.7% (range of 5.8% to 7.1%), near or within the ADA A1C target range. Subjects used insulin lispro in their insulin pumps.
Click: The individual glucose profiles of the 9 patients appear on the graph
Despite excellent A1C levels, these patients experienced wide glucose fluctuations throughout the day as measured with continuous glucose monitoring system (CGMS)
SLIDE BACKGROUND:
CGMS = Medtronic MiniMed Continuous Glucose Monitoring System
Mean duration of diabetes for these 9 subjects was 21.5 years (range 2.5 to 40.4 years).
Glucose Concentration (mg/dL)
200
100
12 AM
4 AM
8 AM
12 PM
4 PM
8 PM
12 AM
Type 1 diabetes, N = 9
24-h CGMS glucose sensor data
Data on file, Amylin Pharmaceuticals, Inc.

10. Relative Contribution of Postprandial Glucose Increases as A1C Approaches Target
100
70%
60%
55%
49%
30% 80
Optional
DISCUSSION POINTS:
Though both fasting and postprandial glucose contribute to overall glycemic control (A1C), the relative contribution of postprandial glucose to overall glycemia increases as the A1C decreases toward the normal range.
On the graph, the teal bars indicate that the contribution of postprandial glucose (relative to fasting glucose) to the A1C increased progressively (30% to 70%) from the highest (>10.2%) to the lowest (<7.3%) A1C quintile.
It is important to note that in the commonly observed range of A1C (approximately 7% to 10%), postprandial glucose had an important contribution (40% to 50%) to the A1C.
SLIDE BACKGROUND:
This study analyzed the diurnal glycemic profiles of 290 patients with type 2 diabetes who exhibited different levels of glycemic control, as measured by A1C.
The patients were treated with diet alone, or with a stable dose of metformin (1700 mg/day), glyburide (5 to 15 mg/day), or both for at least 3 months prior to the study.
Plasma glucose concentrations were determined at fasting (8:00 AM) and during postprandial and post-absorptive periods (at 11:00 AM, 2:00 PM, and 5:00 PM).
Based on these glucose measurements, the investigators calculated the relative contribution of fasting and postprandial glucose to overall glycemic control.
70% 60
% Contribution
51% 40
45%
40%
30% 20
>10.2
<7.3
A1C Range (%)
N = 290; Percentages are approximations
Adapted from Monnier L, et al. Diabetes Care 2003; 26:

11. The Pathogenesis of Type 2 Diabetes An Imbalance of Beta-Cell Workload and Beta-Cell Response
Not Required
DISCUSSION POINTS:
--In type 2 diabetes, the balance of beta-cell response and workload is disturbed as a result of reduced beta-cell capacity to secrete insulin and the increase in beta-cell workload.
--Beta cells secrete less and less insulin in response to elevated glucose, and the first-phase insulin response progressively worsens.
--Many factors that contribute to beta-cell workload are pathologically dysfunctional in type 2 diabetes.
--The result of this imbalance between beta-cell workload and beta-cell response is hyperglycemia.
SLIDE BACKGROUND:
--Contributors to insulin resistance (in addition to obesity) include genetics, age, exercise/physical fitness, dietary nutrients, medications, and body fat distribution.
Hyperglycemia
A; EX 36570
©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

12. Balancing Beta-Cell Response and Beta-Cell Workload Insulin Is Enhanced and Glucagon Is Suppressed
Healthy Subjects (n = 14)
 Beta-Cell
Workload
 Beta-Cell
Workload
 Beta-Cell
Response
Not Required
DISCUSSION POINTS:
--Insulin and glucagon are the counter regulatory hormones of the pancreas that help to control blood glucose.
--This study looked at insulin secretion (beta-cell response) and glucagon secretion (alpha-cell response) after a large carbohydrate meal in healthy, normally glucose-tolerant individuals.
-- Normal glucose homeostasis was maintained by:
--Insulin secretion (beta-cell response), which initially increased and then declined as blood glucose declined
--Decreased glucagon secretion (alpha-cell response) after the meal
--This combination of actions reduced hepatic glucose output during the fed state, as carbohydrate is being absorbed from the GI tract, and euglycemia was maintained.
SLIDE BACKGROUND:
--The carbohydrate meal consisted of 140 g spaghetti, 256 g corn, 252 g rice, 2 medium-sized potatoes (244 g), all of which were boiled, and 2 slides of white bread (26 g). Together, they contained approximately 200 g of carbohydrate.
Euglycemia
Mean (SE)
A; EX 36570
©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

13. Balancing Beta-Cell Response and Beta-Cell Workload Insulin Is Enhanced and Glucagon Is Suppressed
The Pathogenesis of Type 2 Diabetes Beta-Cell Workload Outpaces Beta-Cell Response
Healthy Subjects (n = 14)
Type 2 Diabetes (n = 12)
 Beta-Cell
Workload
 Beta-Cell
Workload
 Beta-Cell
Workload
 Beta-Cell
Response
 Beta-Cell
Workload
 Beta-Cell
Response
Not Required
DISCUSSION POINTS:
--Insulin and glucagon are the counter regulatory hormones of the pancreas that help to control blood glucose.
--This study looked at insulin secretion (beta-cell response) and glucagon secretion (alpha-cell response) after a large carbohydrate meal in healthy, normally glucose-tolerant individuals.
-- Normal glucose homeostasis was maintained by:
--Insulin secretion (beta-cell response), which initially increased and then declined as blood glucose declined
--Decreased glucagon secretion (alpha-cell response) after the meal
--This combination of actions reduced hepatic glucose output during the fed state, as carbohydrate is being absorbed from the GI tract, and euglycemia was maintained.
SLIDE BACKGROUND:
--The carbohydrate meal consisted of 140 g spaghetti, 256 g corn, 252 g rice, 2 medium-sized potatoes (244 g), all of which were boiled, and 2 slides of white bread (26 g). Together, they contained approximately 200 g of carbohydrate.
Hyperglycemia
Euglycemia
Euglycemia
Mean (SE)
A; EX 36570
©2005 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

14. Medication used for DM II
Glucophage (Metformin)
Action is on the liver to decrease extra glucose
Sulfonylureas or Secretagogs (Amaryl, Glucotrol)
Causes the pancreas to produce more insulin
SGLT2 (Invokana,Jardiance)
Off load Glucose from Kidney
Sensitizer (Actos and Avandia)
Makes all of the cells of the body sensitive to insulin
Incretin Family GLP1- mimics hormone naturally found in the body
DPP4 inhibitors (Januvia, Tradjenta, Onglyza) prevent incretin breakdown.

15. Metformin/GLucophage
Biguanide
Dosed 500mg -2000mg QD
Prevents the conversion of glycogen to glucose in the liver
First Line Treatment for Diabetes
Limitations Side effects GI and renal function/clearance
Rarely Metabolic Acidosis since not metabolized in the liver

16. Sulfonylureas Glipizide 2nd Generation (Glucotrol) 2.5m-10mg
Glyburide 2nd Generation (Micronase)
Glimiperide 3rd Generation Pancreatic Specific (Amaryl) 2mg, 4mg and 8mg only in US
By Blocking potassium channels the opening of voltage dependent gates causing calcium influx and insulin degranulation and release. Also may inhibit glucagon and potentiate insulin action at peripheral tissue

17. Meglitinides Starlix –nateglinide 60-120mg daily
Prandin-repeglinide .5mg,1mg and 2mg once daily
Secretagog like but less affinity with the ATP channels and thus a greater disassociation with the receptor when may lessen the rapid out flow of pro-insulin

18. Atypical Orals
Precose- Acarbose alpha glucosidase inhibitor mg TID prior to meals
Bromocriptine-Parlodel dopamine agonist 1.6mg-4.8mg daily
Welchol-Colesevelam bile acid sequestrant doses 6 tablets daily or one packet daily

19. GLp -Incretins Byetta (Exenatide) BID dosing 5mcg and 10mcg
Victoza (Liraglutide) QD Dosing .6mcg-1.8mcg
Bydureon(Exenatide LAR) Q weekly Dosing 2mg
Tanzium (Albiglutide) Q weekly Dosing 30mg and 50mg
Trulicity (Dulaglutide) Q weekly Dosing .75mg and 1.5mg

20. DISCUSSION POINTS:
The increasing plasma glucose resulting from ingestion of 50 g oral glucose (white line in left-side graph) results in an increase of C-peptide (a measure of insulin secretion) (white line in right-side graph).
An isoglycemic intravenous glucose infusion designed to mimic the plasma glucose excursion achieved by the oral glucose load was later administered to the same study patients (orange line in left-side graph). The resulting beta-cell response, measured as C-peptide, is shown on the right-side graph.
Despite the same plasma glucose profiles, there are significant differences in the beta-cell response, as measured by C-peptide.
This difference prompted study into the role of incretins – factors secreted from the intestinal tract, upon the ingestion of food, that enhance the secretion of insulin – that would account for the greater insulin response to oral glucose.
This incretin effect suggested that incretins, and not merely the direct actions of plasma glucose, affect the insulin secretory response.
SLIDE BACKGROUND:
Young, healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic intravenous glucose infusion.
Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in CNS-mediated release of insulin. An early prandial phase, mediated by gut-derived incretin hormones (e.g., GLP-1 and GIP), occurs after food intake but before the ingested nutrients appear in the circulation (or reach the intestinal L cells that secrete GLP-1).
Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted. Therefore, C-peptide serves as a marker for insulin secretion.

21. DISCUSSION POINTS:
The additional insulin response observed with oral vs. IV glucose administration (i.e., the incretin effect) is reduced in subjects with type 2 diabetes compared to healthy subjects.
SLIDE BACKGROUND:
Insulin responses to a 50 g oral glucose load and intravenous glucose infusion designed to mimic glucose concentration profiles after a 50 g oral glucose load were measured in patients with type 2 diabetes (N = 14) and healthy controls (N = 8).
The contribution of incretin factors to total insulin responses (with 100% = response to oral load) was 73% in control subjects and 36% in subjects with type 2 diabetes (P0.05).
The greater beta-cell response observed in subjects with type 2 diabetes during intravenous glucose administration is due to the higher glucose stimulus in subjects with diabetes.

22. DISCUSSION POINTS:
The observation of the “incretin effect” started the search for “incretins” – factors secreted from the intestines that enhance the secretion of insulin in response to the ingestion of food.
Glucose-dependent insulin secretion means enhanced insulin secretion is dependent on elevated blood glucose concentrations, and that when blood glucose concentrations return toward normal, enhanced insulin secretion subsides – hence, the glucose-dependent property.
One of the incretins, glucagon-like peptide-1 (GLP-1) is of special interest, as besides enhancing glucose-dependent insulin secretion (beta-cell response), GLP-1 has other glucoregulatory effects that decrease beta-cell workload.
Upon ingestion of food, GLP-1 is secreted into the circulation by the L cells of the small intestine. This occurs in advance of food directly stimulating the L cells, suggesting that a neural and/or hormonal communication pathway triggers the release of GLP-1 to prepare the body in advance of the absorption of carbohydrates from the meal.
The similarity of GLP-1’s full name with glucagon is only because their amino acid chains are products of the same gene – not because they have similar sites of secretion, actions, or sites of action.
NOTE: Speakers can highlight the differences that are included on the slide itself.

23. DISCUSSION POINTS:
Upon food ingestion, GLP-1 is secreted into the circulation from L cells of small intestine.
GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion.
GLP-1 decreases beta-cell workload and hence the demand for insulin secretion by:
Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload)
Decreasing postprandial glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, which helps to maintain the counterregulatory balance between insulin and glucagon
Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output
Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake
By decreasing beta-cell workload and improving beta-cell response, GLP-1 is an important regulator of glucose homeostasis.
SLIDE BACKGROUND:
Effect on Beta Cell: Drucker DJ. Diabetes. 1998; 47:
Effect on Alpha Cell: Larsson H, et al. Acta Physiol Scand. 1997; 160:
Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997; 160:
Effects on Stomach: Nauck MA, et al. Diabetologia. 1996; 39:
Effects on CNS: Flint A, et al. J Clin Invest. 1998; 101:

24. New Approaches: Incretins for Improved Glucose Control
Two Approaches to Prolonging Incretin Activity
DPP-4 Inhibitors
Incretin Mimetics
Modest HbA1c reduction
Weight neutral
Oral administration
Almost no GI side effects
Very low rate of hypoglycemia
Multiple targets (Preservation of GLP1 activity and GIP activity)
Significant HbA1c reduction
Weight loss
Injection
Higher rate in GI side effects
Low rate of hypoglycemia
Single target (GLP-1)

25. DPP-4 Inhibitors Dipeptidyl peptidase-4 inhibitor
Sitagliptin – Januvia Typical Dose 100mg daily with or without food Secondary doses of 50mg GFR and 25mg for GFR<30 Saxtagliptin- Onglyza Dosing 2.5mg and 5mg if GFR <50 then 2.5mg Linagliptin-Tradjenta 5mg single dosing irrespective of GFR

26. SGLT2 (Glucouretics)
Invokana-(canagliflozin) 150mg GFR>45 300mg GFR>60
Farxiga-(Dapagliflozin) 5mg or 10mg GFR>60
Jardiance-(empagliflozin) 10mg or 25mg GFR>45
Lower the renal glucose threshold by inhibiting SGLT2 receptors in the Kidney causing renal glucose excretion up to 120 grams of glucose

27. SGLT2 Blockade

30. When to cross over to insulin.
No more non-insulin medication to add.
Rising post-meal blood sugars
Increasing hemoglobin A1C (this occurs later)
Very high blood sugars either early on in the disease or later in the advanced disease.
A large percentage of diabetics will require Insulin within years after diagnosis.
SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1
REFERENCE
1. Lantus prescribing information.

31. DON’T BE AFRAID OF INSULIN It’s natural!

32. Modification of Oral when transitioning to Insulin
No need for secretagogs (Sulfonylureas) personal opinion
May continue sensitizers but may increase risk of edema
Metformin may always be continued as long as appropriate (pts still have livers)
GLP1 should always be considered if possible (Fortified with Insulin in Europe)
SGLT2 (Kidney dependent) able to be added at any time to insulin
SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1
REFERENCE
1. Lantus prescribing information.

33. Strive for Ideal: Insulin Regimen
Discussion points
The ideal insulin regimen should strive to match normal insulin secretion patterns.
The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin.

34. Types of Insulin Commonly Used
Once-a-day long-acting Lantus U100/U300 or Levemir or BID NPH
75/25 mix insulin, Novolog 70/30, or Humalog 50/50
Short-acting at meal time Bolus (Humalog, Novolog, Apidra, or Inhaled Affrezza)
Complete transition to insulin using long-acting/short-acting with multiple injections termed Basal/Bolus
Continuous Insulin Infusion using Pumps
SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1
REFERENCE
1. Lantus prescribing information.

35. BasaL only; advantages and disadvantages
Yeas
Ideal for needle scared patients
Less brain cell usage to administer
Nays
Frequently relied upon for too long
Difficult to titrate Fasting Glucose is limiting factor
Not quite physiologic, after all it is a basal
No meal time or post prandial coverage

36. Premixed Insulin Preparations
75/25 mix /70/30 Mix
70%-75% 12 hour long acting and 25%-30% rapid meal time insulin.
Better total day coverage and can be given initially once daily or increased to two times daily.
A more physiologic (better fit) than older 70/30 with Regular. Don’t be stuck in the time warp of the past.
Humalog 50/50
50% long 50% rapid Dosed QD-TID
Basal/Bolus in a Pen
“High Mix”
SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1
REFERENCE
1. Lantus prescribing information.

37. Dosing Low Premix QD initiation begin with Dinner 15-20 units
Monitor Pre meals or 2 hour post prandial for titration
AM fasting elevation will also indicate need for increase dinner dose and PM pre Dinner Blood sugar to increase Breakfast Dose
Augment with rapid with Lunch if Gaps in insulin coverage or transition to 50/50 or Basal/Bolus

38. Scope of Premix Insulin
Advantages
More physiologic in addressing meal time as well as basal
Can start as once daily and work up from there
Titration is possible
Augmenting with rapid acting at lunch
Disadvantages
Fixed Dosing
More awareness needed due to rapid acting
Lunch time can be uncovered in patients who need more comprehensive insulin coverage

39. Intensive insulin management

40. Basal Bolus More Advanced Insulin Plan
Once-a-day long-acting (Lantus, or Levamir BID could replace)
Short-acting insulin
Calculate using CBG levels: start at 1 unit per 50 blood sugar greater than 100 (glucose correction factor)
Grams of carbohydrate: begin with 1 unit per 15 gram of carb. (insulin to carbohydrate ratio)
Testing is the key to being successful
Get assistance from your local CDE’s they are invaluable
SLIDE 2. Lantus is a recombinant human insulin analog indicated for once-daily subcutaneous administration at bedtime in the treatment of adult and pediatric patients with type 1 diabetes mellitus or adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia. It is slowly released after injection, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peaks. This profile allows once-daily dosing as a patient’s basal insulin.1
REFERENCE
1. Lantus prescribing information.

41. Basal-Bolus Insulin Regimen: MDI
Discussion points
The ideal insulin regimen should strive to match normal insulin secretion patterns.
The combination of a long acting insulin to cover the basal dose with rapid acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin.
The basal bolus regimen involves up to 7 blood sugar measurements a day, and 3-4 injections a day, with adjustments necessary to match meal and activity levels.
The use of a rapid acting insulin like Humalog for the bolus injections closely mimics the normal postprandial secretion of insulin.

42. Parting thoughts
The treatment of diabetes is changing rapidly, with new information and insights yearly.
Its a struggle for even the most enthusiastic of providers to stay current on treatment options.
Remember this is a team approach, your education and input is critical for effective treatment.