Mercy Family Practice SC

Diabetes Mellitus Type II

Table of Contents

Introduction

Diabetes Mellitus (DM) has two major types: type I and type II. Type I diabetes mellitus used to be called juvenile diabetes or insulin dependent diabates and Type II used to be called adult onset diabetes or non-insulin dependent diabetes. Those latter terms are no longer used. Since the vast majority of adult medicine deals with type II diabetes mellitus, I will devote this section to this form of the disease.

DM Type II often develops during adulthood. If you have a positive family history of diabetes, as you age over 50 years, and if you gain weight, you have over a 50% chance of developing type II diabetes. As the Baby Boomers now reach well into their older years, we are experiencing a near epidemic of diabetes. Since over 1/3 of our current children are considered overweight, there is little to suggest that this disease will deminish in future years. That is the bad news. The good news is that there are now many treatments available for diabetics.

Pathophysiology

Insulin: Insulin is produced by the beta cell in the pancrease. The main problem in diabetes is a defect in the normal function of the insulin molecule. Insulin is composed of 51 amino acids. It consists of two chains linked by two disulfide bonds. Its main function is to allow glucose (sugar) to enter somatic cells such as a muscle or fat cell. Diabetes is a multifactorial disease which means there are many parts of the process that intefere with insulin to do its job. A misconception is that diabetes type II is a lack of insulin. On the contrary, there often is plenty of insuline. However, there may be defects which prevent the insulin that is present from doing its normal function. All the many facets involved are beyond the scope of this web page. Suffice it to say that for various reasons, diabetes type II is a disease in which there is relative insulin insensitivity which prevents the insulin from working effectively. It may be a defect at the receptor site, or a defect inside the somatic cell.

Figure 1, Insulin Molecule

Cholesterol Molecule
Stick Model of Insulin

Space occupying Model of Insulin

Renal filtration is the process of clearing a substance from the body through the kidneys. I like to use the analagy of making spaghetti. After you boil a pot of spaghetti, one has to strain the water through a collander. Imagine the spaghetti as protein or large molecules and the water as fluid or small molecules. The collander holds the large molecules and the small molecules escape through the holes. The kidney works in much the same way. In figure 2, you can imagine the whole pot of spaghetti is poured into the kidney unit called a glomerulus. This entrance is called the afferent arteriole. Next, the blood travels through a complex of small leaky blood vessels. The glomerular blood vessel holds onto the large molecules and lets pass the small molecules into the glomerular capsule, where they pass downstream into the proximal convoluted tubule, where ultimately they end up in the urinary bladder as urine.

Figure 2, Pathophysiology of Insulin Defect


The Duodenum (first part of the small bowel) and the Liver are the main sources of Glucose; the former from food and the latter during fasting. The Pancrease produces Insulin as a bolus in response to meals and at basel rates during fasting. Due to Insulin defects, represented by the || symbol, Glucose cannot enter the somatic cell, depicted at the far right. Therefore, Glucose builds up in the blood stream.

Glucagon: The production of insulin and its defect is only half the story: glucagon is the other half. For years, physicians only used glucogon to stimulate glucose production from the liver in the treatment of hypoglycemia. Patients whose glucose dropped too low and became less responsive, or unresponsive, got a shot of glucagon to wake them up. Over the years, reasearchers have now discovered their major role in glucose metabolism.

Figure 3, Glucagon molecule


Molecular structure

Stick model

Space occupying model

Glucogon is produced by the alpha cell of the pancrease. Glucagon is released when glucose falls to low. It stimulates the liver to produce glucose and release it into the bloodstream. In the diabetic, there is a defect in which too much glucagon is circulating in the blood stream. This is analagous to pouring gasoline on a fire.

Figure 4, Excess Glucagon Leads to Excess Glucose Production

Below is a discussion of how medications such as DPP-4 and GLP-1 can reduce
Glucagon, leading to the reduction in Glucose production.

Diagnosis

The old definition involved measureing fasting glucose and glucose following a bolus of ingested surger. This was called the glucose tolerance test. In short, if your fasting glucose level was above 120 mg% and your two your post prandial (after ingestion) glucose was above 200 mg%, you were diagnosed with diabetes mellitus. Fortunately this test has been replaced by the Glycosylated Hemoglobin test, also called the Hemoglobin A1c (HbA1c) test. HbA1c is often further abbreviated as A1c.

Since 2010, the American Diabetes Association and others consider this the Gold Standard. It is a random blood sample taken at any time: in other words, you do not have to fast. A normal value is below 6%, and an abnormal result is equal or above 6%. The easiest way to think about this is as follows. The hemoglobin molecule sits inside the red cell. The red cell is bathed in serum of the blod stream where glucose resides. If the red cell environment is high in glucose, then that glucose will diffuse into the hemoglobin molecule and link itself to it. This is called glycosylation. Once a hemoglobin molecule is glycosylated, it remains that way over the lifespan of the molecule.

Because the average life span of a red blood cell is about 120 days, and red cells are being added and subtracted from the blood stream at a constant rate, it is estimated that the HbA1c represents and average of blood glucose over about 2 months time. There is a linear relationship between the HbA1c level and the average glucose found in your blood streem.

Figure 5, Relationship between Glycosylated Hemoglobin (HbA1c) and Average Glucose Concentration in Plasma

The above line can be expressed as an equation: Gluc = 28 x A1c - 42, where Gluc is the glucose level and A1c is the HbA1c level. Once diabetes has been diagnosed, a diabetic should have their HbA1c checked once every three months. In our practice, we send out reminders once every six months.

Dietary Treatment

The first rule is that all diabetics need to follow a diet that reduces carbohydrates (CHO). CHO is a facy way to describe anything that the body can break down into sugar. Examples of CHO include table sugar, and starch, which can be found in bread or spaghetti. It turns out that most of our diet consists of CHO. The other two components include fats and protein. (To see a lengthy discussion about fats, go to the section on cholesterol.)

Current recommendations is that diabetics consume CHO in the form of complex CHO. Examples of this include rye bread or whole grain pasta. The concept here is that you do not want to consume simple CHO that will be broken down into sugar to flood a blood stream that is already is elevated. You want to consume complex CHO that will give the body time to process the glucose. A full discussion of diet is beyond the scope of this web page; however, you may use the following web pages as a resource:

  • American Diabetes Association: Diabetes Meal Plans: link
  • LiveStrong 1800 Calorie ADA Diabetic Diet: link
  • Mayo Clinic Diabetic Diet: link

Medical Treatment

Oral Agents

Metformin

Metformin has been the mainstay of therapy for over 15 years. Metformin is a biguanide, and works by decreasing glucose production from the liver (gluconeogenesis). It also decreases fasting and postprandial glucose concentration. It reduces absorption of glucose in the gastrointestinal tract and it increases insulin sensitivity at the somatic cell in peripheral tissues. Its main side effect is gastrointestinal: it can cause nausea and diarrhea. This is mitigated by giving the medication during meals. Also, there are long acting forms of the medication that may be better tolerated.

Insulin Secretagogues

Insulin secretagogues increase the slow, second phase of insulin secretion from the pancrease. In older patients, they may be associated with hypoglycemia. For decades, sulfonylureas (SU) were the only available insulin secretagogues. Examples of SU are glyburide (DiaBeta, Micronase), chlorpropamide (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol), tolazamide (generic), and tolbutamide (generic). Insulin secretagogues also include the newer agents repaglinide (Prandin) and nateglinide (Starlix). Repaglinide and nateglinide act faster than SU and are less associated with hypoglycemia. Due to their short action, repaglinide and nateglinide need to be given just before mealtime. In general, insulin secretagogues are less effective than TZDs and AGIs.

Dipeptidyl-Peptidase-4 Inhibitors (DPP-4)

Dipeptidyl-Peptidase-4 Inhibitors (DPP-4) have been introduced recently. This is an oral agent that inhibits the DPP-4 enzyme which decreases the metabolism of incretins, glucose like peptide-1 (GLP-1) and gastric inhibitory polypeptide. Inhibition of incretin metabolism will delay gastric emptying which will slow the release of glucose fromthe gastrointestinal tract. GLP-1 is a main incretin. Inhibition of the DPP-4 enzyme decreases metabolism of GLP-1 which increases GLP-1 which in turn decreases glucose levels (see below). Examples of DPP-4 Inhibitors include: Sitagliptin (Januvia) and Saxagliptin (Onglyza).

Thiazolidinediones (TZD)

Thiazolidinediones have been available in the mid-1990s. TZDs work by increasing insulin sensitivity of skeletal muscle and adipose tissue. There are several serious side effects of TZD medications: increase in weight, fluid retention, peripheral edema and congestive heart failure. The first TZD, troglitazone, was discontinued due to the rare cases of liver damage. I tend not to use this medication due to these side effects. The two TZDs now available are pioglitazone (Actos) and rosiglitazone (Avandia).

Alpha-Glucosidase Inhibitors (AGI)

Alpha-glucosidase inhibitors (AGI) inhibit conversion of oligosaccharides into monosaccharides in the intestinal brush border. In other words, large sugar molecules are broken down into small sugar molecules which are necessary to pass throught the small bowel lining into the blood stream. This reduces glucose in the blood stream during digestion. Due to their action in the GI tract, their main side effect is abdominal discomfort, flatus and diarrhea. This is due to the extra sugar being passed downstream to the colon where bacteria (lactobacili) use the sugar as their own food source and produce gas. When used alone, they are not associated with hypoglycemia. Examples of AGI include acarbose (Precose) and miglitol (Glyset).

Injectable Agents

Glucose like peptide-1 Analogues (GLP-1)

Glucose like peptide-1 (GLP-1) is the main incretin hormone which has three effects (a) decreases glucagon production which leads to reduced glucose production from the liver (b) increases beta cell mass and stimulates insulin production from the beta cell of the pancrease, and (c) CNS effects to increase satiety and lead to weight reduction. Examples of GLP-1 are exenatide (Byetta, Bydureon) and liraglutide (Victoza). Exenatide comes from the salivary gland of the Gila monster, which is a highly venomous lizard. Human GLP-1 only stays in the blood stream for 30 to 90 seconds. However, Exenatide is 50% homologous to human GLP-1 but resists inactivation by the DPP-4 enzyme; therefore, it stays in the blood stream for hours. Its major side effect is nausea and emesis which occurs in only a few percent of patients. Currently this category is only available in injectable form.

Insulin

It is useful to know what happend in the normal person. When you are in the fasting state, your body has to produce glucose in a constant rate. You need a basal rate of insulin to accomodate this glucose. It is mandatory for certain organs such as the brain, the heart and the kidneys. However, during a meal, you have a rapid bolus of glucose. The pancrease responds with a rapid bolus of insulin. In Insulin therapy, we try to mimic this as much as possible. The basal rate of insulin is accomplished by the use of long acting insulin. The two on the market are insulin glargine (Lantus) and insulin detemir (Levemir). The bolus of insulin is accomplished by the use of short acting insulin. Both human and analog insulins are available. Human insulin was the first to be released in the market over a decade ago. Analog insulin is favored over human insulin because it binds to albumin in the blood stream for a longer period and is released in an even rate. insulin aspart (NovoLog) is currently the most widely used analog insulin.

Figure 6, Normal Glucose and Insulin Production

In response to mealtime (breakfast,lunch,dinner) you have a bolus of glucose (blue) and a corresponding bolus of insulin (red). This is a simulation.

Alternatively, early on, many diabetics can get by using Lantus and Metformin or Lantus exenatide (Byetta), a GLP-1. This is because the basal insulin is supplied by the Lantus, and the bolus insulin is obtained from the pancrease through the use of an oral agent such as Metformin or Byetta. This works because early on, within eight years of diagnosis, diabetics still have enough insulin production from their pancrease, and the oral agents make that insulin work more efficiently (enhanses insulin sensitivity).

Stratification Based on A1c Level

After diet and weight loss, the second treatment option depends on your Glycosylated Hemoglobin (HbA1c or A1c). A new consensus paper[1] has looked at all the recent literature and has changed the way initial diabetes therapy is considered. The theory is that if your A1c level is low, you have a good chance at reversing the effects of diabetes with aggressive lifestyle changes such as diet, exercise, along with significant weight loss if you are overweight. On the other extreme, if your A1c is very high, you need aggressive control with insulin therapy early since all other measures will fall short of reducing the A1c < 6.0%.

1. A1c <= 7.5%

(a) Monotherapy: It is possible to reduce your A1c level to less than 6.0% with a single agent. Oral agents are often the first choice.

  • Metformin
  • Dipeptidyl-Peptidase-4 Inhibitors (DPP4)
  • GLP-1
  • TZD
  • AGI

(b) Dual Therapy (see below)

2. A1c 7.6 to 9.0%

(a) Dual Therapy: In order to reduce your A1c level to a large degree, it is necessary to combine agents. Often oral agents are tried at first; however, many researchers have suggested to start with Metformin conbined with long acting insulin, such as Lantus or Levemir.

  • Metformin + GLP-1
  • Metformin + DDP4
  • Metformin + TZD
  • Metformin + SU
  • Metformin + Glinide

(b) Triple Therapy: A combination of three oral agents

  • Metformin + GLP-1 + TZD
  • Metformin + DDP4 + TZD
  • Metformin + GLP-1 + SU
  • Metformin + DDP4 + SU
  • Metformin + TZD + SU

(c) Insulin

  • Lantus + Novolog
  • Levemir + Novolog

3. A1c > 9.0%

(a) Insulin alone

  • Lantus + Novolog
  • Levemir + Novolog

(b) Insulin + Oral agents

  • Lantus insulin + Metformin
  • Levemir insulin + Metformin
  • Lantus + Novolog + Metformin
  • Levemir + Novolog + Metformin

(c) Oral agents alone

  • Metformin + GLP-1 + SU
  • Metformin + DPP-4 + SU
  • Metformin + TZD + SU
  • Metformin + GLP-1 + TZD
  • Metformin + DPP-4 + TZD

Figure 7, Algorithm for Treatment of Diabetes

AACE= American Association of Clinical Endocrinologists (click on photo for full resolution)

Liraglutide vs Sitagliptin

There is only one head to head study[2] to compare liraglutide (Victoza) to sitagliptin (Januvia) conducted by Novo Nordisk, the maker of liraglutide. The study was randomized and controled; however, it was unblinded since liraglutide is an injection and sitagliptin is oral. The study enrolled 665 patients and randomly assigned them to three groups and followed them over six months. The study was conducted in 158 sites in 11 countries, including the United States. Patients were only allowed to take Insulin and Metformin, making liraglutide and sitagliptin the independent variables. The results were statistically significant and are shown below. The higher dose of liraglutide was shown superior to sitabliptin in reducing HbA1c levels of approximately 1.5% and weight reduction of approximately 3 lbs.

Figure 8, Liraglutide vs Sitagliptin

Liraglutide vs Exenatide

There is a head to head study [3] that compares liraglutide (Victoza) to exenatide (Byetta) which are both injectable routes. Liraglutide is a GLP-1 analogue where exenatide is a GLP-1 receptor agonist. Both agents act by suppressing glucagon and glucose production during the fasting state. The study was a randomized, 26-week open-label, parallel-group, multinational study. It took diabetic patients with a mean HbA1c above 8.2% and treated each of two groups with either liraglutide or exenatide. The findings show that liraglutide reduced HbA1c levels significantly over exenatide, with p<0.0001. Liraglutide reduced HbA1c levels by -1.12%. The major side effects of liraglutide are nausea and gastrointestinal with a frequency of 8%. On average patients lost 4-5 lbs in weight equally in each group.

Figure 9, Liraglutide vs Exenatide

Tables

Table 1, Antidiabetic Medication by Class

Abbreviation Class Generic Trade Name
AGI alpha-Glucosidase Inhibitor Acarbose
Miglitol
Precose
Glyset
DPP4 Dipeptidyl-peptidase-4 Inhibitor Sitagliptin
Saxagliptin
Januvia
Onglyza
GLP-1 Glucagon-like peptide-1 agonist, Incretin mimetics Exenatide
Liraglutide
Byetta, Bydureon
Victoza
MET Biguanide Metformin Metformin (generic), Glucophage XR, Glumetza, Riomet, Fortamet
SU Sulfonylurea Glyburide DiaBeta, Glynase, Micronase
    Glipizide Glipizide (generic), Glucotrol, Glucotrol XL
    Glimepiride Amaryl
TZD Thiazolidinedione Rosiglitazone Avandia
    Pioglitazone Actos

There are several combination medications available: sitagliptin + metformin (Janumet), pioglitazone + metformin (ActoPlus Met), rosiglitazone + metformin (Avandamet), repaglinide + metformin (PrandiMet), glipizide + metformin (Metaglip and generic), and glyburide + metfonnin (Glucovance and generic).

Table 2, Types of Insulin

Type of Insulin Trade Name Comment
Rapid-acting insulin analogues    
Aspart
Lispro
Glulisine
NovoLog
Humalog
Apidra
Superior to regular human insulin in terms of more rapid action profile with reduced risk of hypoglycemia 2-5 hours after a meal or overnight
Premixed insulin/protamine    
Aspart + aspart-protamine
Lispro + lispro-protamine
NovoLog Mix
Humalog Mix
Usually used twice a day before breakfast and dinner; provides postprandial coverage with 2 injections per day; less flexible than use of basal-bolus therapy with a combination of rapid-acting and long-acting analogues
Long-acting insulin analogues    
Glargine Lantus Can be used with 1 injection per day in patients with type 2 diabetes
  Toujeo SoloStar Concentration 300u/ml (U-300). Available as an insulin pen. This is often used for patients who need a high dose of insulin above 80u per day.
Detemir Levemir Can be used with 1 injection per day in patients with type 2 diabetes; excellent reproducibility of absorption profile within individuals; possibly less weight gain than with other insulins
Degludec Tresiba FlexTouch Concentration 100u/ml (U-100) or 200u/ml (U-200). Available as a pen. This is a long acting insulin. As the dose rises above 80u per day, it may be more economical to use the higher concentration.
Not recommended    
Regular human insulin Humulin R
Novolin R
Onset of action is too slow and persistence of effect is too long to mimic a normal prandial physiologic profile; the result is impaired efficacy and increased risk of delayed hypoglycemia
NPH insulin Humulin N
Novolin N
Does not provide a sufficiently flat "peakless" basal insulin; highly variable absorption even within individuals; increased risk of hypoglycemia compared with the long-acting insulin analogues glargine or detemir

Table 3, Summary of Insulin Regimens

Insulin regimen Components and Frequency of Administration Injections per Day
Basal Glargine,Detemir or Degludec (daily or twice a day) 1 or 2
Premixed NovoLog Mix or Humalog Mix (usually twice a day; occasionally used daily or 3 times a day) 2
Prandial NovoLog, Humalog, or Apidra (usually 3 times a day) 3
Basal-bolus (multiple daily injections) NovoLog, Humalog, or Apidra (usually 3 times a day) in combination with glargine or detemir (daily) 4
Continuous subcutaneous insulin infusion NovoLog, Humalog, or Apidra Continuous

Table 4, List of Oral Medications and Insulin

Generic Brand Dose Onset Duration Price
Biguanides        
Metformin Generic Start 500 mg po bid with meals or 850 mg po qd; Max 1000 mg po bid Half-life: 6.2 h (plasma); 17.6 h (blood) 500 mg #60 $13
850 mg #90 $78
1000 mg #30 $18
Metformin Glucophage same same 500 mg #60: 70
850 mg #60 $114
1000 mg #60: $142
Metformin Generic ER same same 500 mg #90 $21
750 mg #30: $33
Metformin Glucophage XR same same 500 mg #60: $70
750 mg #30: $54
Dipeptidyl-Peptidase-4 Inhibitors (DDP-4)        
Sitagliptin Januvia 100 mg po qd Half-life: 12.4 h 25 mg #90 $646
50 mg #30 $221
100 mg #30 $216
Sitagliptin-Metformin Janumet Start 50-500 mg po bid; Max 50 mg-1000 mg po bid   50-500 mg #60 $217
50-1000 mg #60 $216
Sitagliptin-Metformin Janumet XR Start 100-2000 mg po hs; Max 50/1000 mg 2 tabs po hs   Not available
Linagliptin-Metformin Jentadueto Start 2.5-500 mg po bid; Max 2.5-1000 mg 2 tabs po bid   Not available
Sitagliptin-Simvastatin Juvisync Start 100-40 mg po hs; adjust after 4 wks   Not available
Saxagliptin Onglyza 2.5-5.0 mg po qd Half-life 2.5 h, 3.1 h (metabolite) 2.5 mg #30: $240
5 mg #30: $230
Saxagliptin-Metformin Kombiglyze XR Start 5-500 mg po qd; Max 5-500 2 tabs po qd   2.5-1000 mg #30 $120
5-500 mg #30: $240
5-1000 mg #30: $230
Linagliptin Tradjenta 5 mg po qd Half-life: 12 h 5 mg #30: $230
Glucose-Like Peptide-1 (GLP-1)        
Exenatide Byetta Start 5 mcg sc <1h before meals bid x1mo, then inc to 10 mcg sc bid Half-life: 2.4 h 10 mcg/0.04ml (1 pen, 2.4 ml): $282
5 mcg/0.02ml (1 pen, 1.2 ml): $330
Exenatide Bydureon 2 mg sc qwk Half-life: 2.4 h Not available
Liraglutide Victoza Start 0.6 mg sc qd x1wk then 1.2 mg sc qd, max 1.8 mg/day Half-life: 13 h 18 mg/3ml (1 box, 6 ml): $306
18 mg/3ml (1 box, 9 ml): $432
Long-acting Insulins        
Insulin glargine Lantus Start: 0.5-1u/kl/day sc hs; then adjust according to fasting glucose readings Onset 1h; no peak; duration 24h 100 u/ml (1 vial, 10 ml): $119
100 u/ml (1box, 15ml): $225
Insulin detemir Levemir 0.1-0.2 u/kg sc hs; then adjust as above Onset 5-7h; no peak; duration 24h 100 u/ml (1 vial, 10 ml): $136
100 u/ml (5 pens, 3 ml): $242
Short-acting analog insulins        
Insulin aspart NovoLog Cover meals with 5 units/gram CHO < 15 min before meals; adjust according to the two hour after-meal glucose reading; may add a sliding scale Onset < 0.,25 h, Peak 1-3 h, Duration 3-5 h 100 u/ml (1 vial, 10 ml): $141
100 u/ml (1 box, 15 ml): $258
100 u/ml (5 cartridges, 3 ml): $265
Insulin aspart protamine-Insulin aspart Novolog Mix 70/30 Cover meals with 5 units per gram of CHO * 70% total; adjust according to next pre-meal glucose reading; adjust 30% total according to 12 hour after-meal glucose reading Onset < 0.25 h, Peak 1-2 h, Duration 12-24 h 100 u/ml (1 vial, 10 ml): $138
100 u/ml (5 pens, 3 ml): $258

Abbreviations: / means a ratio such as numerator divided by denominator, u/ml means units per mililiter; # means number as in dispensing;< means less than; bid means twice a day; CHO means carbohydrate; ER means extended release; h means hour; hs means hour of sleep, or bedtime; kg means kilograms; Max means maximum; min means minute; ml means mililiter; po means orally qd means daily qwk means once a week; sc means subcutaneous;tabs means tablets u means units; XR means extended release.

Reference

  1. Rodbard, HW, et al, AACE/ACE Glycemic Control Algorithm Consensus Panel, Endocrine Practice, 15 (6), Sep-Oct 2009, pp 540-559. View Paper and Table
  2. Pratley, RE, et al, Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial, Lancet 2010; 375 pp 1447-56. View Paper, Figures, and Tables
  3. Buse, JB, et al, Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6), The Lancet, July 4, 2009; 374: 39-47. View Paper, Figures and Tables

1500 Heritage Rd Suite A/ De Pere, WI 54115
Hours M-F 8am - 4pm
Phone 920-347-1990 . Fax 920-347-1991