The more I think of it, the more I see that which is diagnosed as “Type 2 Diabetes Mellitus” as a spectrum of metabolic disorders, all of which are capable of producing a single symptom: hyperglycemia. Or maybe two symptoms, if you count beta cell death.
While I am not a doctor, a pharmacist, or trained in medicine or medical research, I can see multiple etiologies (causes and paths to “disease”); each of these should indicate a more specific medical approach to glycemic management and health maintenance. I believe this is why, among the multiple classes of oral antidiabetics, some of them work for some PWDs, but not for others (and vice-versa). If our diagnosing clinicians can split out the various disorders of this spectrum and isolate the causes, I believe they will be able to provide us with more effective management options and better long-term quality of life.
Please note that some of the diagnostic presentations (the group of symptoms the doctor sees) are not unique to a particular etiology, and that an individual’s “Type 2 Diabetes” may be a combination of these factors, requiring a combination of therapies.
The specific etiologies I suggest so far are:
Diabesity. In this case, obesity is the triggering factor. Hormones released by adipose tissues may affect glucose metabolism either by lowering glucose tolerance, by increasing insulin resistance, by stressing beta cells' internal transportation networks (affecting the molecular structure of the insulin produced) or by other pathways yet to be discovered. Insulin insufficiency is a possible finding, as additional body weight suggests additional volume of tissue requiring insulin delivery. (This does not necessarily contradict findings that people with Type 2 diabetes secrete more insulin than people without diabetes. In the absence of these chemical stressors, beta cell function should be close to normal if diagnosis is caught early on.
- The most effective method of managing obesity-triggered hyperglycemia is by weight loss, ideally through diet and exercise, but also through more aggressive approaches such as weight-loss pills and/or bariatric surgery, as appropriate.
- Immediate management methods may include one or more types of oral antidiabetic, accompanied by dietary changes and possibly weight-loss enhancement sidecar drugs.
- Because of their potential for weight reduction, biguanides (such as metformin) and incretin mimetics (such as Byetta) might be first-approach drugs of choice; however, if insulin resistance is also diagnosed, medication more appropriate towards that etiology should be offered instead.
- If diabesity is not caught in its early stages, and is not managed by weight loss, beta cell loss may result, and the archetypical progressive arc, including complications of both hyperglycemia and obesity, may be predicted.
Insulin resistance (IR). I have read of two different types of insulin resistance; there may be more. In the first, the insulin produced is malformed and cannot lock into correctly-functioning insulin receptors. In the second, the insulin receptors are refusing to accept correctly-formed insulin. Recent articles in Hypertension suggest that an excess of certain inflammatory proteases may be related to insulin resistance. Recent research published by the Garavan Institute suggests that the process may be triggered by higher levels of specific plasma lipids' stressing the transportation pathways of beta cells and causing insulin malformation.
- Two different classes of oral antidiabetics target insulin resistance: biguanides increase insulin sensitivity (possibly by their side effect of improving plasma lipid profiles -- see Garavan, above), and thiazolidinediones increase the sensitivity of insulin-receptor sites.
- If it can be determined which type of insulin resistance a patient is facing, the correct class of corrective agents can be prescribed.
Impaired glucose tolerance (IGT). This mode of hyperglycemia, suggested by nondiabetic fasting glucose levels paired with higher than expected fructosamine and HbA1c results -- or definitively diagnosed by Oral Glucose Tolerance Test (OGTT), may result from the delayed digestion of carbohydrates (such as may occur in gastroparesis and related digestive conditions), through insufficient insulin production, through loss of first-stage insulin response, or from other causes.
- Remediation of mild IGT-based hyperglycemia may be possible through diet (lowered per-meal carbohydrate consumption) and and exercise.
- Carbohydrate hypersensitivity may possibly be lowered through the effects of alpha-glucosidase inhibitors.
- Insulin insufficiency may respond to insulin secretagogues (sulfonylureas, DPP-4 inhibitors, meglitinides, and d-phenylalanine derivatives) -- first-phase insulin insufficiency may respond better to the non-sulfonylurea secretagogues).
- Treatment of underlying digestive conditions should also remediate IGT.
Insulin insufficiency. Beta cells are normal, but insulin production is low. Insulin is correctly-formed, there is no issue with insulin receptors. Fasting glucose is elevated and OGTT may or may not show delays in
digestion. Patient may not be obese.
- This is famously one of a handful of specific MODY presentations which has been successfully treated by low-dose insulin secretagogues.
- Nonautoimmune hyperglycemia often presents a signature drop in "first phase insulin response". This may respond better to incretin mimetics or DPP-4 inhibitors.
High "natural" setpoint. In this case, there are no obvious causes for hyperglycemia (patient presents with low body-fat percentage, non-fatty liver, correctly-formed insulin, no change in c-reactive proteins to suggest beta-cell death, no problems with insulin receptors, oral glucose tolerance test comes back within tolerance ranges, normal blood lipid profile, no genetic markers for MODY) -- but the patient's blood glucose levels remain elevated. In this case, modern medicine presumes that something is causing too much glucose to remain in the bloodstream.
- In this presentation, appropriate treatment would appear to be that of addressing and lowering the "setpoint". Until a specific causality for this speculated mode of hyperglycemia, the presumed appropriate care would be to actively monitor blood glucose levels in the "prediabetic" range, or to treat more advanced cases with one of the classes of oral antidiabetics that inhibit glucagon production (e.g., biguanides).
Again, I’m not a doctor, a pharmacist, a CDE, or qualified in any way to make medical pronouncements. I’m just a person with
diabetes who does a lot of reading and who is sometimes able to discern possible patterns from small amounts of data.
If any of my speculations can be used to improve the level of care and the outcomes of those diagnosed with
nonautoimmune hyperglycemic spectrum disorders (or prediabetes or borderline diabetes or Type 2 diabetes or NIDDM),
then I will have contributed positively to the dialog.