The Four Types of Ketosis Prone Type 2 Diabetics

There are four types of KPD T2's
.Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes

It is classified by antibodies and pancreatic capacity. This seems obscure but it isn't very hard.Analysis of clinical, phenotypic, and genotypic data derived from this prospective characterization of multiethnic, heterogeneous, ketosis-prone diabetic patients indicates the presence of novel forms of ß-cell dysfunction as well as a classification scheme to categorize these patients. We propose four groups based on two important features commonly used to distinguish type 1 and type 2 diabetes: presence or absence of biological markers of ß-cell autoimmunity, and presence or complete absence of ß-cell functional reserve. This is not meant to be rigid classification, but rather a hypothesis-testing scheme to differentiate etiologically and clinically distinct forms of ketosis-prone diabetic syndromes, and thus to uncover novel forms of ß-cell dysfunction. The distinctive pathogenetic features and diagnostic implications of the four Aß groups are discussed individually below.

A+ß- group
Patients in this group, with significantly low ß-cell functional reserve together with circulating ß-cell autoantibodies, are likely identical with the well-defined form of autoimmune type 1 diabetes. They had early onset diabetes and were generally lean. African-American patients predominated in this group. The results of the HLA analysis supported the contention that these patients have typical autoimmune type 1 diabetes. Irrespective of ethnicity, certain HLA allelic variants are found in high frequency in persons with autoimmune type 1 diabetes (19, 24, 25, 26, 27, 28, 29, 30,31). The proportion of patients with the type 1 diabetes susceptibility HLA alleles DQB1*02 and DQA*03 was significantly higher in the A+ß- group than in the three other groups, including the phenotypically similar A-ß- group. Furthermore, no A+ß- patients were positive for the protective HLA alleles DRB1*15 and DQB1*0602 (19, 32, 33, 34, 35, 36). All patients in this group required multiple daily insulin injections to avoid ketosis 12 months after the episode of DKA, and a significant proportion had recurrence of DKA during this period despite close monitoring by the study team.
A-ß- group
Patients in this group are likely to have diverse pathogenic mechanisms leading to ketosis-prone diabetes, including potentially novel forms of nonautoimmune ß-cell failure. There were numerous similarities in clinical characteristics and ß-cell functional reserve between the A+ß- and A-ß- groups (Table 2 and Figs. 2–4). At first glance, the difference between these two groups appeared to lie solely in their autoantibody status. However, HLA analysis revealed that there were also major differences between these two groups in genetic susceptibility to ß-cell autoimmunity. The frequencies of one class II allele (DQB1*02), which is strongly associated with autoimmune type 1 diabetes susceptibility (24, 29, 32, 37), and of another (DQA*03), which is in linkage disequilibrium with the strong susceptibility alleles DQB1*0302 and DQB1*0301, were low in the A-ß- group compared with the A+ß- group (Fig. 4). These features make it likely that the A-ß- group consists primarily of persons with nonautoimmune mechanisms of ß-cell injury, rather than persons with autoimmune type 1 diabetes whose circulating autoantibody levels have declined over time to undetectable levels (38). No A+ß- patients were positive for the protective allele DQB*0602 (33, 35, 39), whereas 9% of A-ß- patients possessed this allele. (There were no statistically significant group differences in the frequency of DQB*0602, however, probably because of the small sample sizes as well as the relatively low prevalence of the DQB*0602 allele in the general population (40). A-ß- patients also were more likely to have first-degree relatives with type 2 diabetes. The current classification scheme of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (41) would tend to place patients in the A-ß- group into the clinical category of idiopathic type 1 diabetes, a category that begs further definition, as provided by the criteria presented here.
A+ß+ group
Some patients in this group may represent a variant of what several reports of European cohorts have termed antibody-positive type 2 diabetes (42, 43, 44) or latent autoimmune diabetes ofadults (45, 46). However, others in the A+ß+ group likely represent a more aggressive form of late-onset autoimmune type 1 diabetes than described in these reports. DQB1*02 may be a marker for the more aggressive subset of A+ß+, because the six A+ß+ patients with DQB1*02 had higher mean HbA_1c (8.6 ± 2.5%) than those without DQB1*02 (6.5 ± 0.6%) after 12 months of close management (P = 0.05). Furthermore, five of the six patients with DQB1*02 still require insulin treatment to avoid ketosis after 12 months of follow-up, whereas insulin has been discontinued safely in four of the five A+ß+ patients who lack this allele (P = 0.03). Although analysis of a larger cohort of A+ß+ patients is needed to confirm this suggestive trend, this combination of class II HLA and autoantibody markers may represent an important diagnostic opportunity to identify A+ß+ patients destined to have a more aggressive course. Because the presence of both the genetic markers and autoantibodies should precede the onset of clinical manifestations, it may be possible to identify such patients before their ß-cells are irreversibly destroyed (47).
A-ß+ group
This is the largest group of ketosis-prone patients, comprising the greatest number with new-onset diabetes. The frequencies of the autoimmune type 1 diabetes susceptibility HLA allelesDQB1*02 and DQA*03 are low in this group. A-ß+ patients appear clinically heterogeneous, with a wide range of BMI (Table 2). A-ß+ patients have achieved good glycemic control within 6 months of follow-up, and half have been able to discontinue insulin treatment.
The causes of severe, acute ß-cell dysfunction leading to DKA are likely to be diverse in this group. Half the A-ß+ patients have new-onset diabetes, without a notable precipitating factor for DKA. The mean HbA_1c of this subgroup at presentation with DKA was 13.9 ± 2.2, indicating a relatively long period of undetected and untreated hyperglycemia. It is possible that the cause of acute ß-cell failure in these patients was glucotoxicity (48, 49, 50) or lipotoxicity (51), which reversed with excellent control of glycemia after the episode of DKA. The sustained, preserved ß-cell functional reserve and glycemic improvement in these patients argue against the likelihood that they have a form of type 1 diabetes with the poorly defined honeymoon period (52). In fact, all A-ß+ patients have now been evaluated for more than 1 yr, and one third for more than 2 yr, and they continue to maintain uniformly excellent glycemic control (mean HbA_1c  7.0%) with adequatefasting levels of C-peptide (1.25 nmol/liter). The subset of A-ß+ patients with previously diagnosed diabetes may comprise patients with long-standing forms of type 2 diabetes with progressive ß-cell failure (53, 54) of such causes as ß-cell apoptosis (55), islet cell amyloid (56), or iron infiltration (57).
Three previous studies have measured islet cell autoantibodies and ß-cell function in subsets of African-American patients presenting with DKA (5, 6, 7). The patients described in these studies (e.g. those with "Flatbush diabetes") would fit into our two ß+ groups. Consistent with our ß+ group data, the mean age at diagnosis of these African-American cohorts was in the fifth decade, the mean BMI was high, only a minority had ß-cell autoantibodies, and glycemic control improved markedly after intensive treatment. These similarities add support to the concept of the A-ß+ group as manifesting a distinct form of ketosis-prone diabetes, but our data extend the expression of this syndrome to patients of Hispanic, Caucasian, and Asian ethnicity.
HLA genotyping was particularly helpful in distinguishing autoimmune-associated from probable nonautoimmune-associated forms of ß-cell dysfunction within the class of patients with low ß-cellfunctional reserve (i.e. in distinguishing the A+ß- and A-ß- syndromes). In the initial analysis, the class II alleles selected were those known to be strongly associated with autoimmune type 1 diabetes in multiple ethnic groups, e.g. the positively associated DQB1*02 and DQB1*0302 (22, 24, 27, 58, 59, 60, 61, 62, 63) and the negatively associated DQB1*0602 (19, 23, 32, 33,35, 39). In the pair-wise comparison, there was a clear difference in the relative frequencies of DQB1*02: high in the A+ß- group (72%) and low in the A-ß- group (26%). The frequency of DQB1*0302 showed a trend in the same direction, but did not attain significance after Bonferroni adjustment (which may not be necessary, because the association between this allele and autoimmune type 1 diabetes is well established). The protective allele DQB1*0602 (64) was absent in all patients in the A+ß- group, but present in 9% of A-ß- patients. DQB1*0602 is a low-frequency allele in the general population of Caucasian-Americans (5–13%) and African-Americans (4–15%) (40), hence a larger sample of patients would be necessary to have the power to detect group differences in its frequency. Interestingly, DQA*03, an allele not frequently reported to be associated per se with autoimmune type 1 diabetes susceptibility, also distinguished the A+ß- group (89%) from the A-ß- group (44%). DQA*03 is known to be in linkage disequilibrium with the strong susceptibility alleles DQB1*0302 and DQB1*0301, hence its frequency distribution is likely to represent a real difference in susceptibility to autoimmunity between the A+ß- and A-ß- groups.
The absence of features of autoimmune diabetes or HLA-associated susceptibility to autoimmune diabetes in the A- groups raises the possibility that they could include persons with geneticcauses of ß-cell dysfunction, such as syndromes of maturity onset diabetes of youth (MODY) or mitochondrial transfer RNA mutations. The MODY syndromes are characterized by Mendeliandominant inheritance due to monogenic mutations (65). Although there are at present no reported cases of subjects with documented MODY gene mutations presenting with ketoacidosis, this is certainly a possibility. Sixty-four (86%) of the patients in our A- cohort have a family history of type 2 diabetes, 45 of these with a potentially dominant mode of transmission. Screening of theextended pedigrees for linkage to the currently known MODY genes is ongoing. Diabetes associated with mitochondrial gene mutations also involves defects in glucose-stimulated insulin secretion (66). However, the absence of evidence for maternal transmission of diabetes and other typical features (e.g. deafness, neurologic disorders, cardiac or renal failure) make it unlikely that any of our patients harbor known mitochondrial gene mutations.
Imagawa et al. (67) have described a cohort of lean Japanese subjects who developed new-onset, fulminant ß-cell failure of apparently nonautoimmune cause after a relatively short period of hyperglycemia (HbA_1c < 8%). Our two A- groups do not appear to include such patients, inasmuch as all of our A- patients, including those who were of new onset, had significantly higher HbA_1c levels, a less fulminant course, greater BMI and higher frequency of first-degree relatives with diabetes. Furthermore, it is not clear that the Japanese patients were truly nonautoimmune,because they possessed HLA haplotypes (DRB1, DQA1, DQB1 0405,0303,0401, or DQB1 0901,0302,0303, or 0802,0401,0302) known to be associated with autoimmune type 1 diabetes (68, 69, 70).
The clinical course of the two ß- groups highlights the critical importance of ß-cell functional reserve in achieving effective glycemic control. Although both ß- groups experienced significant (3%) decreases in HbA_1c and marked declines in the rate of hospital readmissions for DKA as a result of the study intervention, their chronic glycemic status remained quite poor. Other factors, such as lack of compliance with insulin treatment, could also have played a role in this outcome. We did not systematically record treatment compliance, but it is well-known that treatment noncompliance is particularly severe and glycemic control is especially difficult to achieve in type 1 diabetic patients in indigent, minority-ethnic, urban settings in the United States (42, 43, 44).
In conclusion, we have used a heterogeneous, multiethnic cohort to demonstrate that patients presenting with DKA comprise at least four distinct diabetic syndromes that are separable byautoantibody status, HLA genotype, and quantitative assessment of ß-cell function. Novel, nonautoimmune causes resulting in variable degrees of ß-cell dysfunction are likely to underlie the A-ß+ and A-ß- syndromes. Detailed genotypic and phenotypic characterization studies of patients in these categories are ongoing, in the hope that they will specify the etiologic bases of the syndromes revealed by the present analysis. The current data are also of clinical relevance to the evaluation and prognosis of patients with ketosis-prone diabetes. ß-Cell functional reserve at the time ofDKA is the strongest indicator of future metabolic control, but GAD and IA-2 autoantibody status and class II HLA allelotypes can assist in classifying ketosis-prone patients and improvingprediction of clinical outcomes.

Syndromes of Ketosis-Prone Diabetes Mellitus

http://edrv.endojournals.org/cgi/content/full/29/3/292
Ketosis-prone diabetes (KPD) is a widespread, emerging, heterogeneous syndrome characterized by patients who present with diabetic ketoacidosis or unprovoked ketosis but do not necessarily have the typical phenotype of autoimmune type 1 diabetes. Multiple, severe forms of β-cell dysfunction appear to underlie the pathophysiology of KPD. Until recently, the syndrome has lacked an accurate, clinically relevant and etiologically useful classification scheme. We have utilized a large, longitudinally followed, heterogeneous, multiethnic cohort of KPD patients to identify four clinically and pathophysiologically distinct subgroups that are separable by the presence or absence of β-cell autoimmunity and the presence or absence of β-cell functional reserve. The resulting "Aβ" classification system of KPD has proven to be highly accurate and predictive of such clinically important outcomes as glycemic control and insulin dependence, as well as an aid to biochemical and molecular investigations into novel causes of β-cell dysfunction

IV. Classification of KPD

TopAbstractI. IntroductionII. Case ReportsIII. History of KPDIV. Classification of KPD V. Natural History and...VI. Pathophysiology of KPD...VII. Management of KPDVIII. Conclusion and ProspectsReferences

To date, attempts to differentiate patients with KPD into clinically distinct and relevant subgroups have resulted in four different classification schemes: the ADA classification, a BMI-based system, a modified ADA classification, and the Aβ system.
The first is contained within the ADA’s most recent classification of diabetes in general (15) and has been adopted by investigators at the University of Texas Southwestern Medical School (Dallas, TX). All patients who experience DKA are defined as having type 1 diabetes, and among this group those who lack autoantibodies are referred to as "idiopathic type 1" or "type 1b." Strictly interpreted, the ADA scheme would define patients with both type 1a and type 1b diabetes as insulin dependent, because it does not mention possible reversion to insulin independence in either category; however, the Dallas group considers patients with type 1b to behave more like patients with type 2 diabetes, with some becoming insulin-independent. A second scheme is that developed by investigators at Emory University (Atlanta, GA) who separate KPD patients into lean or obese (9). "Lean KPD" patients are those with clinical characteristics of type 1 diabetes with low β-cell function, whereas "obese KPD" patients are those with clinical characteristics of type 2 diabetes with some preservation of β-cell function. A modification of the ADA scheme is used by investigators at the University of Paris who divide KPD patients into three groups (20). Patients with β-cell autoantibodies are classified as type 1a just as in the ADA scheme, whereas those who lack autoantibodies are distinguished retroactively, based on long-term insulin dependence, into "KPD insulin-dependent" (KPD-ID) and "KPD non-insulin dependent" (KPD-NID). Both type 1a and KPD-ID patients have clinical characteristics of type 1 diabetes with poor β-cell function, whereas subjects with KPD-NID have clinical characteristics of type 2 diabetes with preserved β-cell function for a prolonged duration.
Our collaborative group at Baylor College of Medicine and the University of Washington has used a classification system that distinguishes four KPD subgroups based on the presence or absence of autoantibodies and the presence or absence of β-cell functional reserve (Aβ classification) (1). The four subgroups are: A+β– (patients with autoantibodies and absent β-cell function); A+β+ (those with autoantibodies but preserved β-cell functional reserve); A–β– (those without autoantibodies but absent β-cell function); and A–β+ (those without autoantibodies and preservedβ-cell functional reserve). A+β– and A–β– patients are immunologically and genetically distinct from each other but share clinical characteristics of type 1 diabetes with very low β-cell function, whereas A+β+ and A–β+ patients are immunologically and genetically distinct from each other but share clinical characteristics of type 2 diabetes with preserved β-cell functional reserve (Fig. 1and





There will be a test on this later so please read up.

Mike

The obesity epidemic or what's up with all the fat people.

Most likely, if you're reading this, you're diabetic and you're overweight. You might have tried diets and lost a little bit or a lot but you probably gained it back and have pretty much learned to live with it. This isn't all that unusual unfortunately. We are in an unprecedented epidemic of obesity with rising diabetes.

The usual prescription is for more exercise and cutting the calories. The basic prescription has at its base the biblical idea of gluttony and sloth. If you are fat, you feel shame. I'm going to row against the tide on this one with something called "common sense".

I will start with the single principle that all humans are animals and that the basic principles of being a living being applies to all living beings. The idea I wish to bring forth from here has to do with eating and this idea is this: animals eat because they are hungry and they stop eating when they are not.

Now you could bring up various animal experiments about fat mice and rats and how they will eat long after they are so fat that they can't stand and other bizarre displays but I didn't mention obesity. I only said that:animals eat because they are hungry and they stop eating when they are not. I didn't mention obesity because I don't think it's relevant to the discussion. Obesity, I have come to believe, is a symptom and not a cause.

If obesity is not a cause but a symptom, what's the cause? Hunger! Yep, hunger. I'm putting forth the proposition that we are in the midst of famine.

My youngest boy is exhibit A. He was a poor college student who went to school in his hometown so he was able to scrounge food from family and friends. His typical procedure was to arrive for dinner and then try to eat - forever. He would sit and eat until he was full and then, not knowing where his next meal was coming from, would continue to try and put food away. It was horrible to watch. He would slowly chew with a mild revulsion on his face then swallow. No matter how hard he tried, he could never seem to get beyond a few fork fulls before he had to give up.

This isn't news. Eating after you're full is very hard and the thought of doing it over and over again makes you feel green. Try it. You can't do it. But you might say that you've seen people overeat all the time. Once again, stick with the idea. I didn't say people don't overeat. I said that it is nearly impossible to eat, if you aren't hungry.

I am exhibit B. For the last thirty years, I have been a bike rider. What ever I had to do, I would try to do it on a bike. I would put somewhere between four thousand and five thousand miles a year on a bike. I ate carbs like crazy in order to do this because carbo loading was the thing to do when you were putting in a lot of physical exertion. My reputation for absolute gluttony is based on this. I was never fat but I could eat plate after plate of food. I ate until my stomach was full and then ate some more but I remained hungry. This was my life. I couldn't stop eating because I was famished.

You can't diet, if you're hungry. It will only make you hungrier. You can't excercise when you're hungry because your body cuts back on motion. You can, however, grow fat because there really isn't a connection between appetite and obesity.

I hear the experts talk about empty calories, large portions and too many snacks but rats, no matter the density or type of calories, would stop eating. Hunger is basic and at a level far below regard.

Stole this from Peter of HyperLipid

Here

Now I'll say it again: we eat because we are hungry not out of some lascivious need. What we are seeing now is hunger, one that isn't slacked by eating. Something has gone wrong with our diet and we are now hungry at a level that causes us to eat in search of a satiation which we can't achieve.

Mike

Western Diet Implicated in African American Diabetes

PUT THE SODA DOWN, NOW!

Okay, now that I've got your attention, I want to tell you why. Diabetes has a very large footprint in the African American community and researchers have been looking for the reason why. Here I have a novel paper that says that it is genetic and that we are the victims of the FDA food pyramid. To put it concisely, people of African descent have a problem with processing carbohydrates at a genetic level. This may very well be the cause of a good deal of the metabolic problems noted in African Americans.

Stable Patterns of Gene Expression Regulating Carbohydrate Metabolism Determined by Geographic Ancestry

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008183#pone.0008183-Lindquist1

Individuals of African descent in the United States suffer disproportionately from diseases with a metabolic etiology (obesity, metabolic syndrome, and diabetes), and from the pathological consequences of these disorders (hypertension and cardiovascular disease)...

...Differences in expression of several carbohydrate metabolism genes suggest both genetic and transcriptional mechanisms contribute to these patterns and may play a role in exacerbating the disproportionate levels of obesity, diabetes, and cardiovascular disease observed in Americans with African ancestry.

The KPD's I've spoken to all have lamented their problems with post prandial spikes. This specifically refers to the hour after a person has taken their first bite of a meal. This blood sugar should never go over 140. A normal blood sugar doesn't and there is a very good reason why. Research has shown this is the point where damage begins to occur throughout the body.

This link is to "Blood Sugar 101": http://www.phlaunt.com/diabetes/14045678.php . It is run by Janet (Jenny) Ruel and any time you spend there will be profitable if you're really interested in the ins and outs of diabetes.

If you have a genetic problem handling carbohydrates and have the added problem of being Ketosis Prone this combination will eventually move you into hyperglycemia and / or DKA. The eating of carbs will force your blood sugar up which will create glucostoxicity. This is glucose poisoning. Beta cells in the pancreases of KPD's are very sensitive to this and will slowly shutdown. The more carbs ingested the worse the condition will come and god help you, if you drink soda or juice to try to slack your thirst because they are almost pure carbs and filled with High Porn Corn.

The truth is there is almost no average American meal that will not push your blood sugar beyond the 140 mark. I can't handle better than 20 grams of carbs at any setting and those carbs need to be very complex to keep me from spiking my blood sugar. Even the supposedly healthy diet is problematic here. Whole grains, potatoes, brown rice, apples, bananas, oranges and pastas are just a few things that I have to avoid.

This doesn't match what you would get from a dietitian but you have to recognize that most of the research has been done on Europeans and the minority communities have not been factored into this. Some might claim this is racism but it more neglect than anything. We, much like the LADA and MODY community, must look after ourselves here. I've got one more piece of the puzzle that I want to put out and then I can really lay this out in a logical fashion.

Mike

Ketosis Prone diabetes as a MODY

It has been one of my conclusions that KPD is a type of MODY which shows up unannounced and then works its wickedness undetected for years. The italics are mine.

Endocrinol Metab Clin North Am. 1999 Dec;28(4):765-85.

Monogenic diabetes mellitus in youth. The MODY syndromes.

Winter WE, Nakamura M, House DV.

Department of Pathology, Immunology, University of Florida College of Medicine, Gainesville, USA. winter.pathology@mail.health.ufl.edu

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.

Winters is one of the original investigators of KPD and has written extensively on it.