More Diabetes - A Disease by Any Other Name?

This post is somewhat a followup on a post of mine from over a year ago entitled  Diabetes - A Disease by Any Other Name?  The post was mostly inspired by a comment Jenny Ruhl of the Blood Sugar 101 site made in her first podcast interview with Jimmy Moore - to paraphrase:

Diabetes is no more a disease than to say "cough" is a disease.

I tend to agree with the above in the current context of the term diabetes being synonymous with hyperglycemia, as opposed to defining it as pancreatic dysfunction.   This is because many diseases/disorders are called diabetes that just so happen to be characterized by, among other things, the symptom (manifestation) of hyperglycemia (fasting and/or postprandial).  Indeed Jenny herself is a MODY (Maturity Onset Diabetes of the Young), a relatively rare genetic form of diabetes with an underlying defect that has been identified.  Jenny cannot be cured with current treatments because her disease is inherent.    Thus her hyperglycemia (symptom/manifestation) can be likened to a cough, but her diabetes (genetic anomaly) cannot.  I hope that makes sense.  

Perhaps there will come a day when the medical community can somehow come together to reclassify the various forms of diabetes into individually named disorders -- maybe even dropping the term diabetes entirely from all but the most classic of cases, the Type 1.  This would be a monumental task, and diabetes is such an ingrained term in the vernacular that I don't think it can be done.  But if anything would go further towards finding out the specific causes, best treatments and/or possible cures for the constellation of pathologies currently lumped together as diabetes, sorting it all out may just be the ticket!  As it stands now, we've got Type 1 and everyone else.  The everyone else used to be Type 2, until they started coming across all of these people presenting with symptomatic profiles (fasting & postprandial hyperglycemia/insulin sensitivity/beta-cell functionality) that didn't quite fit either the classic T1 or the majority of T2's.  We call them 1.5's.  It seems to me that the T1.5's are the truly underserved by the medical establishment as they are relatively small in number.  Roughly 5% is the number I've seen most commonly for diagnosed 1.5's, while the misdiagnosed T2's (and to a lesser extent T1's) who are really 1.5's would inflate this to as high as 20% of the diabetic population.   And yet even the use of "1.5" is misleading in terms of classifying the disease state because this is a symptomatic/manifestation descriptive rather than a true etiological/pathological distinction.  They just fall somewhere between the T1 and T2 on the symptomatic profile landscape.  The current T1.5 designation includes LADA (Latent Autoimmune Diabetes of Adults) and MODY types.

That's not so bad, right?  Well, did you know that not even every MODY is the same?  That's right.  There are SIX different MODY's that have been identified.  I recently came across the following paper: 

MOLECULAR MECHANISMS AND CLINICAL PATHOPHYSIOLOGY OF MATURITY-ONSET DIABETES OF THE YOUNG

I'm laying some groundwork here vis a vis the role that hyperglycemia per se plays in complications vs. the underlying mechanisms that manifest in hyperglycemia.  The MODY's are true "diabetics" if we define diabetes as beta cell dysfunction.  They all share a genetic defect in some protein transcription factor in the beta cell that ultimately impacts insulin secretion.  I'll discuss these in greater detail in another post (or more), but want to give you one image from this paper showing all of the possible genetic anomalies in the beta-cell that are at play in the various MODY diseases.   All but one are nuclear transcription factors, with the exception being a defect in glucokinase transcription.

Caption:  Glucose is transported into the beta cell by a specific glucose-transporter protein (GLUT-2) on the cell surface. The MODY-associated glycolytic enzyme glucokinase (associated with MODY 2) catalyzes the transfer of phosphate from ATP to glucose to form glucose=6-phosphate. By means of this reaction, glucokinase functions as the glucose sensor of the beta cell.  The generation of ATP by glycolysis and the Krebs cycle leads to inhibition and closure of the ATP-sensitive potassium channels (the target of sulfonylurea drugs), depolarization of the plasma membrane, opening of the voltage-dependent calcium channels, and influx of extracellular calcium and mobilization of calcium from intracellular stores, leading to the fusion of insulin-containing secretory granules with the plasma membrane and the release of insulin into the circulation. A mutation in one of the alleles of the gene encoding glucokinase leads to a reduction in beta-cell glucokinase activity, resulting in decreased glucose phosphorylation in the beta cell and glucose-stimulated insulin release at any blood glucose concentration. The MODY-associated transcription factors — hepatocyte nuclear factor (HNF) 4α (associated with MODY 1), HNF-1α (MODY 3), insulin promoter factor 1 (IPF-1 [MODY 4]), HNF-1β (MODY 5), and neurogenic differentiation factor 1 (NeuroD1), or beta-cell E-box transactivator 2 (BETA2 [MODY 6]) — function in the nucleus of the beta cell and regulate the transcription of the insulin gene (either directly, as in the case of HNF-1α, HNF-1β, IPF-1, and NeuroD1 or BETA2, or indirectly, through effects on the expression of other transcription factors, as in the case of HNF-1α); they also regulate the transcription of genes encoding enzymes involved in the transport and metabolism of glucose as well as other proteins required for normal beta-cell function.

The MODY-2's caught my eye in this paper, and I've been accumulating PDF's on this disorder.  It's quite rare, being a small subset of the MODY's who are already a small percent of diabetics.  This is a very stable form of "mild diabetes" -- mildly elevated FBG and IGT on an OGTT -- with mild hyperglycemia*, that is not associated with many of the complications usually found in diabetics.  *Keep in mind that in medical vernacular, mild hyperglycemia means fasting levels over 100 mg/dL and 2 hr OGTT's in the 140-to-200 mg/dL range.  They often have normal HbA1c's. 

I'm going to leave it at that for today, but I would like to make one more point vis a vis discussions on blood sugar levels, diabetes, and diet -- carbohydrate restrictive or otherwise.  The MODY types, especially, do not appear to be environmentally provoked.  In this way they are similar to some knockout animal models, where the young animals are indistinguishable from normal ones, but their phenotypes develop with age -- some faster than others, but generally predictably.  So too for MODY -- some of whom are diabetic at birth, and others who while "young" do not develop diabetic symptoms until puberty or even their 20's.  The issue is WAAAAAAAAAAAAAAY more complicated than the teaspoon crowd would like everyone to buy into (which makes one wonder why they would want that ....)