Type 2 Diabetes Classification - A Straw Man Scale for Progression

Many people in the diabetes online community (DOC) are concerned about the label "prediabetes", its predecessor term "borderline diabetes", and its colloquial counterparts (e.g., "a touch of the sugar"). The prevailing attitude is that one either has diabetes, or one does not. This may seem counterintuitive to the general understanding that a woman who was diagnosed with gestational diabetes (GD), but whose postpartum glucose metabolism has returned to reference normal (RN), does not have Type 2 diabetes mellitus (T2DM), but is at increased risk for developing T2DM later in life. It also contrasts with the popular belief -- even espoused by some in the mainstream medical community -- that if a person diagnosed with T2DM can bring his glucose metabolism back to RN by changes to his diet and exercise regimen (D&E) without the use of antidiabetic medications, then he no longer has diabetes.

Two biases of significant note: (1) current medical understanding is that at the point of T2DM diagnosis, a person has lost 50% of beta cell function (AACE, p. 16), and (2) the diabetes online community is primarily informed by persons with Type 1 diabetes mellitus (T1DM), an autoimmune disorder for which there is currently no cure.

Based on the above attitudes and biases, the belief would be that the new mother, having been diagnosed with GD during pregnancy, would be considered to have T2DM, even if it can be mediated without frank lifestyle adjustments. Similarly, the person who was diagnosed with T2DM is considered to still have T2DM, even if it is mediated completely by D&E.

Unlike most presentations of T1DM, T2DM is currently understood to be a progressive condition. Our understanding of its progression in a given individual is informed by both quantitative and qualitative benchmarks. The most common quantitative benchmarks are the individual's fasting blood glucose level, serum fructosamine level, and amount of glycosylated hemoglobin. Other quantitative benchmarks -- such as c-peptide level -- may be useful in determining both insulin resistance and degree of remaining beta cell function. Qualitative benchmarks include signs and symptoms of known complications of diabetes at all levels of their development.

One analogy for cataloguing the degree of progression of T2DM is that used for cataloguing hypertension or cancer: a stage chart. In Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), hypertension is categorized from consistently slightly-elevated blood pressure ("prehypertension") through progressively elevated levels, and the response of those levels to pharmacotherapy.

An initial straw man chart can be derived from the American Association of Clinical Endrocrinologists' Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus (2007) examples for initial pharmacotherapy of T2DM:

Classification of Type 2 Diabetes Mellitus (based on initial therapy algorithms)

Progression Level	HbA1c (untreated)
Stage 1 (Prediabetes)	5.7 - 6.4
Stage 2	6.5 - 7.0
Stage 3	7.0 - 8.0
Stage 4	8.0 - 10.0
Stage 5	> 10.0

Other issues that play into determining the progression of T2DM include the deterioration of endogenous insulin production, the development of complications of diabetes, and the degree to which a person's blood glucose levels and HbA1c are responsive to pharmacotherapy. A more complex table of progression might include these in a manner such as this:

Classifications of Type 2 Diabetes Mellitus (proposed)

Level	HbA1c (Goal)1	Effective Therapy	Evidence of Complications	c-peptide (relative)
Stage 1 (Pre-Diabetes)2	< 6.03	ILM. Oral medication optional for aggressive treatment.	none	high
Stage 2	< 6.5	Oral medication and/or insulin sensitizer required	none	high
Stage 3	< 7.0	Combination therapy and/or insulin required	possible; possible comorbid conditions	varies
Stage 4	< 7.0	Insulin therapy required, with or without oral medications and/or pramlintide (Symlin)	probable; possible comorbid conditions	low
Stage 5	< 8.0	Intensive insulin therapy required, possibly in conjunction with insulin sensitizers	obvious; one or more comorbid conditions	low

1 While the HbA1c goals at the more advanced levels of diabetes progression are high enough that complications are likely to develop or intensify, those goals may not be realistically achievable with current medical and pharmaceutical technology.
2 Includes all previous diagnoses of gestational diabetes or Type 2 diabetes in which pharmacotherapy is not currently indicated
3 More aggressive practitioners may argue for an HbA1c goal of under 5.5 for Stage 1, under 6.0 for Stage 2, and under 6.5 for later stages of T2DM. The less-aggressive goals are informed in part by the (ACCORD) study, in which the tested combination therapy suggested a higher mortality risk for intensive control.

A classification scheme of this sort may remove the ambiguity of a diagnosis of "prediabetes" and its associated laissez-faire ("It's not diabetes") attitude, as well as the popular belief that once diagnosed, one can become "undiagnosed" (or perhaps "de-diagnosed"). It can also alert a medical practitioner to the need for ongoing monitoring and assessment of a person's glucose metabolism. On the other hand, classification will add to the pool of people indicated to have diabetes those who do not consider themselves to be currently affected by diabetes -- and in an environment where a positive diagnosis can mean the denial of employment, medical insurance, or healthcare, this can have worse repercussions than living with undiagnosed or untreated Stage 1 (or even Stage 2) T2DM.

Making it Easier for Patients to Help Themselves

Text messages could hasten tuberculosis drug compliance
Original source: The Lancet Volume 373, Issue 9657
Authors: Eliza Barclay
Publication date: 3 January 2009
DOI (digital document ID): 10.1016/S0140-6736(08)61938-8
Requires subscription? No
Publicly-available abstract: No

Synopsis:
The use of SMS (Short Message System) technology is examined as an option for improving patient compliance in terms of taking pills for the treatment of tuberculosis. Techniques examined include text messages to cellphones with follow-ups if the patients do not respond to the messages, pill bottles with SIM cards that alert a central server when the bottle has been opened (ostensibly for the patient to take the medication), asking patients to speed-dial a special cellphone number after taking their medication, or asking patients to text back a code from a post-medication urine test. The use of financial and other incentives to follow the regimen is also discussed.

Reliability:
The compliance techniques are currently being investigated. The letter does not address the possibility of false compliance (response to the message without taking the medication; opening the pill bottle without removing a pill; speed-dialing the appropriate phone number without taking the medication).

Practical Applications:
While these techniques are being investigated for the management of tuberculosis patients in Africa, there are many people in industrialized nations who don't take their medications because they forget, or because they have not correctly processed a change in their medication regimens, or because they have so many medications that it is difficult to keep track of which one to take when. This is particularly, but not exclusively, true of elderly patients. There are also patients who don't correctly take their medications for economic reasons.

People with Type 2 diabetes, who are often on several medications in addition to those for glycemic control, fall into this category. In addition, many of us don't test as often as we should, or log our blood glucose readings reliably.

Some insurance companies and hospitals offer a reminder service where they phone these groups of patients to remind them to take their medications. The SMS techniques discussed in this letter may be useful either as adjuncts to the phone-reminder services, or as a new service where none currently exists.

This synopsis was based on the complete article.

Can combined oral therapy improve muscular fitness?

Combined thiazolidinedione–metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle
Original source: Diabetologia Volume 52, Number 1
Authors: N. Temofonte, M. P. Sajan, S. Nimal, T. Pastoor, C. Fumero, L. Casaubon, J. L. Powe, M. L. Standaert1, and R. V. Farese (corresponding author)
Publication date: January, 2009
DOI (digital document ID): DOI: 10.1007/s00125-008-1180-z
Requires subscription? Yes
Publicly-available abstract: Yes

Synopsis:
Impaired insulin responses in Type 2 diabetes can make it difficult for glucose to get to muscles, where they are needed. It is believed that this is because certain insulin-activated protein enzymes (atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt)) are not as thoroughly activated as they should be. Both metformin and thiazolidinediones (a class of oral diabetes-management drugs that includes rosiglitazone (Avandia) and pioglitazone (Actos)) improve this deficiency. The investigators wanted to know if adding both drugs together would create an even greater improvement.

Combined metformin-thiazolidinedione therapy was administered to Type 2 test ubjects for 5-6 weeks and the results measured. The investigators observed improved glucose movement and improved insulin-induced activity of four muscle signalling factors (insulin receptors plus two protein kinases). Despite this improved activity, the levels of aPKC in muscle tissues were not improved.

Because of the improvement in the four signalling factors, the investigators consider this test successful.

Reliability:
The number of patients tested was not available in the abstract, nor was any CONSORT statement, so it's difficult to tell whether the sample size was large enough to counteract small-sample skew. Several of the investigators are associated with a Veteran's Administration (VA) center. VA patients often get the worst possible levels of care, so it is hard to tell how far along the subjects' T2 had progressed, or how well it had been treated before the test. That we are looking at combined therapy and it is being called "therapeutically useful" even though depressed muscular aPKC levels were not affected by the treatment suggests that this is the sort of experiment that would be funded by a drug manufacturer, with an eye towards pushing more expensive drugs (such as Avandamet, a combination of Avandia and metformin) on the T2 public.

Practical Applications:
Improved muscular uptake of glucose could improve physical performance, and with it, positive incentives toward exercise. This could result in T2 patients being more interested in exercising, and thereby, improving both physical fitness and insulin sensitivity.

This synopsis was based on the abstract only.