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Ketosis-Prone
Type 2 DM
郝 立 智 醫 師
永康榮民醫院新陳代謝科
Guillermo E. Umpierrez, Dawn Smiley,
and Abbas E. Kitabchi.
Ann Intern Med.
2006 Mar 7;144(5):350-7.
(From Emory University School of Medicine, Atlanta, Georgia, and
University of Tennessee Health Science Center, Memphis, Tennessee.)
Outline
•
ABSTRACT
•
INTRODUCTION
•
Historical Background
•
Prevalence
•
Clinical Presentation
•
Clinical Course
•
Immunogenetic Studies
•
Genetic Studies
•
Metabolic Studies
•
Function of the ß Cell
•
Insulin Action
•
Management
•
SUMMARY
ABSTRACT
•
Several investigators have reported that more than half of
African-American persons with new diagnoses of DKA have clinical, metabolic,
and immunologic features of type 2 DM during follow-up.
•
These p'ts are usually obese, have a strong family history
of DM, have a low prevalence of autoimmune markers, and lack a genetic
association with HLA.
•
Their initial presentation is acute, with a few days to
weeks of polyuria, polydipsia, and weight loss and lack of a precipitating
cause of metabolic decompensation.
•
At presentation, they have markedly impaired insulin
secretion and insulin action, but intensified diabetic management results in
significant improvement in ß-cell function and insulin sensitivity sufficient
to allow discontinuation of insulin therapy within a few months of follow-up.
•
On discontinuation of insulin therapy, the period of
near-normoglycemic remission may last for a few months to several years.
•
The absence of autoimmune markers and the presence of
measurable insulin secretion have proven useful in predicting
near-normoglycemic remission and long-term insulin dependence in adult p'ts
with a history of DKA.
•
This clinical presentation is commonly reported in African
and African-American persons but is also observed in Hispanic persons and those
from other minority ethnic groups.
•
The underlying mechanisms for ß-cell dysfunction in
ketosis-prone type 2 DM are not known; however, preliminary evidence suggests
an increased susceptibility to glucose desensitization.
INTRODUCTION (1)
•
In 1987, Winter and colleagues reported a small cohort of
young African-American p'ts who, despite presenting with severe hyperglycemia
or DKA, subsequently had clinical and metabolic features of type 2 DM.
•
Obesity was present in 46% of these p'ts, and their insulin
secretion in response to mixed-meal stimulation was intermediate between that
seen in nondiabetic controls and in p'ts with type 1 DM. They called this form
of DM: atypical DM.
•
During the past decade, this clinical presentation of DM has
been increasingly recognized and is believed to account for 25% to 50% of
African-American and Hispanic persons with new diagnoses of DKA.
•
Although most cases are reported in African persons and in
African-American individuals in the United States, atypical DM has also been
reported in Native-American, Japanese, Chinese, Hispanic, and white
populations.
INTRODUCTION (2)
•
Because of the mixed features of type 1 and type 2 DM, this
variant of type 2 DM has been referred to in the literature as DM type 1B,
idiopathic type 1 DM, atypical DM, Flatbush DM, type 1.5 DM, and more recently,
ketosis-prone type 2 DM.
•
The aims of this review are to review current information
regarding the clinical presentation, metabolic and immunologic features, and
pathogenesis of ketosis-prone type 2 DM and to share our experience in the
management of adult p'ts with this "atypical" form of the disease.
•
We did a computerized search of biomedical journal
literature from MEDLINE, PubMed, and Ovid from 1966 to October 2005.
•
We reviewed English-language original and review articles
found under the subject headings ketosis-prone type 2 DM and atypical
DM.
Historical Background
•
During the past 5 decades, case studies from Nigeria, Congo,
Tanzania, and other sub-Saharan countries have reported small series of p'ts
with atypical presentation of DM.
•
In the 1960s, Adadevoh and Dodu reported that some adult
p'ts with DKA were able to discontinue insulin therapy after a relative short
time and remain in near-normoglycemic remission for several months to years.
•
This unique, transient insulin-requiring profile was
recognized mainly in p'ts with newly diagnosed DM and was reported as
"temporary DM in adult Nigerians."
•
Subsequent reports from other African groups noted the
difficulty in classifying such p'ts as having type 1 and type 2 DM during their
initial presentation.
•
In the United States, an "atypical" form of DM was
first reported in 12 African-American youths.
•
Ten of these p'ts were admitted to the hospital with DKA,
and 2 were admitted with severe hyperglycemia. The DM in these p'ts was
characterized by an acute presentation, an autosomal dominant pattern of
inheritance, negative islet-cell antibodies, and an insulin response to mixed
meals that was intermediate between that seen in nondiabetic controls and in
p'ts with type 1 DM.
•
In contrast to the long-term insulin requirement of type 1
DM, these p'ts discontinued insulin therapy and maintained acceptable glycemic
control for many years either by diet or by taking oral agents.
•
In 1994, Banerji and colleagues reported 21 p'ts with DKA
who had similar characteristics except for older age at onset and a lower
prevalence of obesity.
•
All of these p'ts were black, were mostly of Caribbean
origin, and were labeled as having Flatbush DM in recognition of the region in
New York where most of them resided.
•
The researchers also recognized the presence of measurable
pancreatic insulin reserve, absence of autoimmune indicators of ß-cell
destruction, and increased frequency of HLA-DR3 and HLA-DR4.
•
Subsequently, our group reported on the clinical, metabolic,
and immunogenetic features of 2 large cohorts of black p'ts presenting with
unprovoked DKA.
•
We showed that p'ts with ketosis-prone type 2 DM have a
severe but transient defect in insulin secretion and insulin action, which partially
resolves after a few weeks of insulin therapy and is followed by
near-normoglycemic remission that may last for several months to years.
Prevalence
•
Not known, but observational studies suggest that this type
of DM accounts for a substantial number of p'ts with DKA.
•
In the USA, the prevalence has been estimated to be between
20% and 50% in African-American and Hispanic p'ts with new diagnoses of DKA.
•
In addition to ethnicity, clinical features predictive of
future near-normoglycemic remission are obesity and a family history of type 2
DM.
•
Among 154 consecutive(連續不斷的)
African-American p'ts admitted to the hospital with DKA, we observed that
obesity was present in 29% and that the prevalence of obesity was higher among
those with newly diagnosed DM (56%).
•
More
than 80% of p'ts have a family history of type 2 DM. The mean BMI at
presentation in African-American p'ts with ketosis-prone type 2 DM has ranged
between 28 kg/m2 to 37 kg/m2.
•
A
high rate of obesity is also reported in Hispanic and Chinese persons and in
sub-Saharan black African immigrants to Europe.
• Obesity in persons with DKA from
minority ethnic groups is more common than in white persons, in whom the rate
of obesity is less than 20%.
•
Balasubramanyan and colleagues reviewed the clinical
profiles of 141 adults admitted to the hospital with DKA. At presentation, 39%
of p'ts were considered to have type 1 DM, 53% were considered to have type 2
DM, and 8% were not classified. 28 % of p'ts had newly diagnosed DM, 93% of
whom were reassessed at least 2 years after their initial episode of DKA and
were considered to have type 2 DM.
•
More recently, Piñero-Piloña and Raskin reported that the
incidence of this type of DM among persons with new-onset DM with DKA was
approximately 60%.
•
In agreement with the U.S. experience, African studies have
reported that 42% to 64% of p'ts with DKA initially treated with insulin
therapy do not have classic type 1 DM and may experience prolonged remission.
•
The prevalence of ketosis-prone type 2 DM seems to be lower
in Asian and white persons and may represent fewer than 10% of cases of DKA.
Clinical
Presentation
•
Most adults with ketosis-prone type 2 DM are obese,
middle-aged persons with newly diagnosed DM who present with unprovoked(無故的) DKA (Table 1).
•
The initial presentation is usually acute. These p'ts have a
history of polyuria, polydipsia, and weight loss for less than 4 to 6 weeks.
•
The mean age at diagnosis is 40 years (SD, 2) (range, 33 to
53 years). More than three fourths of p'ts with ketosis-prone type 2 DM present
as having new-onset DM.
•
Several series of p'ts with ketosis-prone type 2 DM show a
2- or 3-fold higher prevalence in men.
•
This is in contrast to series of white p'ts with type 1 DM,
which report that women are more likely than men to develop DKA.
•
The male predominance in ketosis-prone type 2 DM seems to be
independent of the degree of obesity and age at presentation.
•
The reason for the sex difference is unknown; however, it
has been attributed to hormonal factors, body fat distribution, and changes in
insulin sensitivity .
•
Physical examination reveals signs of dehydration, dry
mucous membranes, and tachycardia.
•
Substantial hypotension or changes in mental status are
seldom seen at admission. Glucose level and acid–base parameters at
presentation are similar to those reported in lean p'ts with DKA.
•
In our series, the mean level of glucose at admission has
ranged between 38 to 40 mmol/L (684 to 720 mg/dL), with a mean serum
bicarbonate level of 12 to 14 mmol/L, pH level of 7.22 to 7.25, and hemoglobin
A1c level between 12% and 14%.
Factors
associated with discontinuing insulin therapy after diabetic ketoacidosis in
adult diabetic p'ts
•
AIMS: To assess the factors associated with successful
discontinuation of insulin therapy after diabetic ketoacidosis (DKA) in adult
p'ts.
•
METHODS: P'ts (≧18 years)
attending the Endocrine and Metabolism Clinic at a major hospital in southern
Taiwan were recruited. After recovery from the acute stage, those with no
contraindications to oral antidiabetic agents, with adequate beta cell reserve,
and with no antiglutamic acid decarboxylase (GAD) antibody were treated with
oral agents.
•
RESULTS: Sixty-six p'ts (38 males, 28 females, aged 18-76 years)
were included, and 21 qualified for treatment with oral agents. These 21 p'ts
were older at diagnosis of diabetes (45.5 +/- 14.0 vs. 40.0 +/- 13.8 years, P =
0.047), had shorter diabetes duration (median 0 vs. 5.5 months, P = 0.040),
higher BMI (median 23.4 vs. 19.5 kg/m2, P < 0.001), higher serum osmolality
during DKA (352.1 +/- 40.7 vs. 318.0 +/- 16.4 mmol/kg, P = 0.005), and lower
insulin dose following recovery (median 0.49 vs. 0.83 unit/kg/d, P < 0.001)
than those p'ts that had to continue insulin therapy. Thirteen p'ts (8 males, 5
females; 62%) successfully discontinued insulin for at least one year without recurrence
of DKA. Multiple logistic regression analyses showed that BMI ≧ 25 kg/m2 (adjusted relative risk (ARR)
8.85, 95% CI 1.05, 8.39), diabetes onset age ≧ 40 years (ARR 8.08, 95% CI 1.16, 6.95), and undiagnosed
diabetes before DKA (ARR 8.90, 95% CI 1.19, 7.51) were significant factors
associated with successful discontinuation of insulin therapy.
•
CONCLUSION: We identified three independent
clinical factors associated with successful discontinuation of insulin therapy
after DKA.
Clinical Course
•
Few studies have analyzed the clinical course and predictors
of near-normoglycemic remission in adults with DKA (Table 2).
•
McFarlane and colleagues described the clinical course of
African-American persons from Brooklyn admitted to the hospital with newly
diagnosed ketoacidosis who were followed for at least 1 year.
•
Remission was defined as a A1c level of 6.3% or less and a
FPG of less than 6.6 mmol/L (<120 mg/dL) 3 months after therapy with all
pharmacologic agents was discontinued.
•
42 % of p'ts achieved remission after a mean of 83 days and
remained in remission during 20 months of follow-up.
•
There were no differences in age, sex, plasma glucose level
at presentation, changes in BMI, magnitude of weight change, or pharmacologic
agents used between p'ts who achieved remission and those who did not.
•
We also observed that near-normoglycemic remission was
achieved in 70% of obese African-American p'ts after 9 weeks of follow-up.
•
More recently, Mauvais-Jarvis and colleagues reported that
discontinuation of insulin therapy with subsequent remission was achieved in
76% of sub-Saharan African p'ts with DKA after a mean of 14.3 weeks (range, 1
to 150 weeks) of insulin therapy.
•
Ten years after their first presentation, 40% of p'ts did not
require insulin injections.
•
P'ts with DKA who achieve remission frequently have
recurrence of hyperglycemia or ketosis if treated with diet alone after
discontinuation of insulin therapy.
•
Two studies reported that 60% and 67% of p'ts with ketosis-prone
type 2 DM relapsed into hyperglycemia within 2 years if treated with diet alone
.
•
In such p'ts, treatment with sulfonylurea or metformin has
proven effective in prolonging the duration of normoglycemic remission and in
preventing readmission for ketoacidosis.
•
Other investigators, however, have observed a limited and
unpredictable response to OHAs and have recommended long-term insulin treatment
in p'ts with ketosis-prone type 2 DM.
•
Weight loss before the initial admission is common in obese
p'ts with DKA, but additional weight loss does not seem to predict the ability
of these p'ts to achieve near-normoglycemic remission. Mean weight loss before
admission ranges between 4 and 12 kg.
•
In our series, among p'ts who achieved remission, one third
continued to lose weight, one third maintained their weight, and the remainder
regained the initial weight lost.
Immunogenetic Studies
•
Several
groups have reported on the prevalence of autoantibodies to islet cells,
insulin, glutamic acid decarboxylase, and protein tyrosine phosphatase in p'ts
with ketosis-prone type 2 DM (Table 1).
•
The
rate of positive autoimmune markers has ranged between 0% and 18%.
•
The
prevalence of autoantibodies in obese African-American p'ts with DKA (17%) is
similar to that in obese p'ts with nonketotic hyperglycemia (16%) but is
substantially lower than in lean p'ts with type 1 DM who have DKA (66%).
•
The rate of positive autoantibodies seems to be similar to
that reported in p'ts with type 2 DM.
•
This subset of p'ts with positive autoantibodies is
recognized as having latent autoimmune adult DM or slowly progressing type 1
DM.
•
During follow-up, most p'ts with latent autoimmune DM have
features of insulin dependence, including a propensity toward developing
ketosis and complete ß-cell failure.
•
Of interest, p'ts with ketosis-prone type 2 DM and positive
autoantibodies have considerably reduced basal and stimulated insulin secretion
compared with those with negative autoantibodies and are more likely to relapse
into hyperglycemia and to become insulin dependent.
Genetic Studies
•
Analyses of relative frequencies of HLA alleles in
ketosis-prone type 2 DM have produced conflicting results. Most investigators
have failed to find an association with HLA susceptibility alleles.
•
In contrast, others have found an increased frequency of
HLA-DR3 and HLA-DR4 compared with nondiabetic populations.
•
Maldonado and colleagues reported on the association of HLA
class II genotype and the presence of positive autoantibodies in a cohort of
p'ts with DKA. They found that p'ts with positive autoantibodies have a higher
frequency of DQA*03 and DQB1*02, 2 alleles strongly associated with
susceptibility to autoimmune type 1 DM; however, the frequency of these HLA
alleles was low in p'ts with negative autoantibodies.
•
Because most p'ts have negative autoimmune markers, HLA
association may not be a prominent feature of ketosis-prone type 2 DM.
•
Although genetic susceptibility to ketosis-prone type 2 DM
is likely, it is not known whether the model is polygenic or has a major gene
influence.
•
A point mutation Gly574Ser in the HNF1-α gene was proposed as a marker of ketosis-prone type 2 DM in
African-American children and adolescents, but a recent report in adults
excluded this association.
•
Recently, a missense mutation (Arg121Trp) of PAX4 has been
implicated(牽連) in early and
insulin-deficient type 2 DM in Japanese p'ts.
•
PAX4 is a transcription factor that is essential in the
differentiation of embryonic pancreatic progenitors into insulin-producing ß
cells in the mammalian pancreas.
•
Japanese persons who carry the Arg121Trp variant are
characterized as having either transient insulin dependence at DM onset or a
rapid evolution toward insulin deficiency, suggesting that mutations of PAX4
lead to severe ß-cell dysfunction in humans.
•
Recently, an R133W mutation in PAX4 was identified
(homozygous in 4% and heterozygous in 27%) in a West African population with
ketosis-prone type 2 DM.
•
Because R133W heterozygosity has also been found in 15% of
West African persons with type 2 DM, in 22% of West African nondiabetic
controls, and in 14% of African-American controls, but was not in white persons
(0%), this abnormality in the PAX4 gene may be more population-specific
than causal.
Metabolic
Studies-Function
of the ß Cell
•
The insulin response to oral and IV glucose load, test meals,
and nonglucose secretagogues has been reported after resolution of
ketoacidosis, at normoglycemic remission, and during follow-up in p'ts with
ketosis-prone type 2 DM.
•
We measured ß-cell function shortly after resolution of
ketoacidosis or hyperglycemia and at normoglycemic remission in a large group
of obese African-American p'ts with DKA with similar hyperglycemia levels but
without ketosis. Their mean glucose level at admission was greater than 33
mmol/L (>600 mg/dL).
•
IV glucose infusion 1 day after resolution of ketoacidosis
did not evoke(引起) any insulin
response; however, improvement of metabolic control resulted in insulin levels
that were 3-fold higher than those obtained during the initial test.
•
Pancreatic insulin reserve determined by changes in
C-peptide levels after glucagon stimulation, both 1 day after resolution of DKA
and after 12 weeks of follow-up, is shown in the Figure.
• Figure. Levels of plasma C-peptide
before and after glucagon stimulation (1 mg IV) in p'ts with ketosis-prone type
2 DM.
–
Insulin
secretion was assessed 1 day after resolution of DKA (at presentation) and
after 10 weeks of follow-up.
–
Data
are expressed as means and SDs.
–
Acute
insulin response to glucagon is the incremental change in C-peptide level over
the baseline level.
–
To
convert values to nmol/L, multiply by 0.333.
•
After resolution of hyperglycemia, basal and stimulated
C-peptide levels in obese p'ts with DKA were statistically significantly
greater than those in lean p'ts with DKA but were lower than those in obese
p'ts with type 2 DM and similar levels of hyperglycemia levels but without
ketosis.
•
During follow-up, obese p'ts with DKA had substantial
improvement in basal and stimulated C-peptide levels, but the acute insulin
response remained lower than in obese nondiabetic controls.
•
Recent studies have reported similar insulin responses in
p'ts with ketosis-prone type 2 DM and estimated that p'ts who achieved
normoglycemic remission had an 80% improvement in fasting and stimulated
C-peptide levels, whereas those who did not achieve remission lost 60% of their
insulin-secreting capacity.
•
These
findings indicate that the impaired ß-cell function in p'ts with ketosis-prone
type 2 DM cannot be attributed to irreversible ß-cell damage but can be
attributed to transient functional abnormalities of the ß cells.
• Although the underlying
mechanisms are not known, investigators have hypothesized an increased
susceptibility to ß-cell desensitization due to elevations of plasma glucose
(glucose toxicity) or sustained elevation of free fatty acid levels
(lipotoxicity).
•
To
investigate the pathogenesis of acute ß-cell failure, we have studied susceptibility
to glucose toxicity and lipotoxicity in obese African-American p'ts with
ketosis-prone type 2 DM.
•
The
function of the ß cells was assessed by changes in levels of insulin and
C-peptide during a 20-hour glucose infusion (200 mg/m2 per min), and
a 48-hour infusion of Intralipid (Pfizer Inc, New York, 20% solution at 40 mL/h)
plus heparin infusion (250 U/h) to increase levels of FFA in obese p'ts.
Dextrose infusion rapidly increased levels of C-peptide by 4- to 5-fold during
the first 10 hours; thereafter, insulin secretion progressively decreased.
•
After
20 hours of glucose infusion, levels of insulin and C-peptide were lower than
preinfusion baseline levels.
• However, increasing FFA levels
by 3-fold during the 48-hour Intralipid and heparin infusion was not associated
with a deleterious effect on insulin secretion.
•
Chronic
hyperglycemia has been associated with impaired insulin secretion in animal
models in which ß-cell mass has been surgically reduced or glucose levels were
increased by continuous infusion.
•
Studies
done on humans have also shown that ß-cell function improves after
hyperglycemia is relieved by successful DM therapy.
•
Although
the pathogenesis of glucose toxicity is not completely understood, it seems
that chronic hyperglycemia induces a generalized downregulation of the
glucose-processing system that leads to impaired ß-cell function and
insulinopenia.
•
Recent
evidence indicates that the impaired ß-cell response involves a reduction in
the insulin and PDX-1 gene expression.
• Pancreatic duodenal homeobox
factor-1 (PDX-1) is a key transcriptional factor that regulates gene
transcription in response to glucose.
Insulin
Action
•
Assessment of insulin sensitivity by using the euglycemic
hyperinsulinemic clamp and the minimal model approach have indicated that
shortly after admission to the hospital, glucose disposal is markedly depressed
in p'ts with ketosis-prone type 2 DM compared with weight-matched controls.
•
During follow-up, improvement of metabolic control resulted
in a 200% improvement in insulin action and insulin sensitivity increased to
levels not significantly different from those in obese healthy p'ts.
•
More recently, studies in Chinese persons and sub-Saharan
black African persons confirmed the severe but transient impairment of insulin
action.
•
Chronic hyperglycemia has been shown to impair insulin
action and glucose uptake in peripheral tissues.
•
The mechanism by which chronic hyperglycemia causes impaired
insulin sensitivity is not completely understood but probably relates to an
alteration in insulin signaling at the postreceptor level.
•
Using muscle biopsy specimens obtained within 2 days of
resolution of ketoacidosis and during near-normoglycemic remission from p'ts
with ketosis-prone type 2 DM, we studied the pattern of Akt-1 and Akt-2
expression and insulin-stimulated phosphorylation.
•
We observed that hyperglycemia selectively decreases Akt-2
expression and insulin-stimulated phosphorylation on the serine residue without
affecting threonine phosphorylation.
•
Improved metabolic control resulted in 70% greater Akt
expression in muscle during near-normoglycemic remission than during the
hyperglycemic period.
•
Insulin signaling upstream of Akt-2 did not seem to be
involved as insulin-receptor phosphorylation, and expression of insulin
receptor, insulin-receptor substrates 1 and 2, and
phosphatidylinositol-3-kinase were unchanged.
•
Altered expression of Akt-2 at presentation was accompanied
by reduced expression of many other signal transduction proteins, increased
expression of enzymes counterregulatory to insulin action, and a pro-apoptotic
pattern of protein expression.
•
These results provide evidence that diminished Akt-2
activation is a critical mechanism for hyperglycemia-induced insulin resistance
in skeletal muscle.
Management
•
Successful therapy for DKA requires aggressive fluid and
electrolyte replacement and administration of insulin, followed by careful
scrutiny(詳細的檢查) for
precipitating factors for metabolic decompensation.
•
Our protocol for inp't management of obese p'ts with DKA is
shown in Table 3.
•
The use of this protocol resulted in resolution of
hyperglycemia by a mean of 6 hours and resolution of ketoacidosis by 12 to 14
hours.
•
After resolution of DKA, subcutaneous multidose insulin
treatment is started at a dose of 0.8 U/kg of body weight.
•
The insulin dose is adjusted to achieve fasting and premeal
blood glucose levels less than 6.6 mmol/L (<120 mg/dL).
•
Because
of the initial ß-cell dysfunction and insulin resistance, insulin requirements
are higher during the first 2 to 4 weeks, with a mean insulin dose of 1 to 1.2
U/kg. Thereafter, insulin requirements progressively decrease.
•
We
recommend tapering insulin doses once levels of FPG remain less than 6.6 mmol/L
(<120 mg/dL) for 2 weeks or if hypoglycemia occurs.
• When this protocol is followed,
approximately 70% of obese p'ts with new diagnoses of DKA are able to discontinue
insulin therapy after a mean follow-up of 9 weeks.
•
After discontinuation of insulin therapy, if p'ts are
treated with diet alone, hyperglycemia frequently occurs within 2 years of
follow-up.
•
Low-dose sulfonylurea and metformin treatment prolong the
duration of remission for 24 to 40 months.
•
Some investigators, however, have raised concerns about the
use of sulfonylurea in p'ts with ketosis-prone type 2 DM, especially in those
with positive autoantibodies.
•
A 10-year prospective study compared the effect of small
doses of subcutaneous insulin versus low-dose sulfonylurea treatment in the
progression of ß-cell dysfunction in Japanese p'ts with ketosis-prone type 2 DM
who had islet cell antibodies. Seroconversion of autoantibody status from
positive to negative occurred in 80% of p'ts shortly after initiation of
insulin therapy, but islet-cell autoantibodies remained positive in all p'ts
treated with sulfonylurea.
•
In addition, the response of C-peptide to glucagon improved
statistically significantly after 6 and 12 months in the insulin-treated group
but decreased progressively in the sulfonylurea-treated group.
•
Assessment
of insulin secretion has been helpful in predicting near-normoglycemic
remission in obese p'ts with a history of DKA.
•
Most
investigators recommend IV glucagon stimulation to assess pancreatic insulin
reserve. For this test, C-peptide levels are measured before and at 3 or 6
minutes after the administration of glucagon (1 mg).
•
Basal
and stimulated C-peptide levels greater than 0.33 nmol/L and greater than 0.5
nmol/L shortly after presentation, and greater than 0.5 nmol/L and greater than
0.75 nmol/L during follow-up, predict remission in p'ts with a history of DKA.
•
Clinical and genetic studies indicate that ketosis-prone
type 2 DM is not a subtype of maturity-onset DM of the young or tropical
fibrocalculous DM.
•
Maturity-onset DM of the young is an autosomal dominant form
of DM, which usually develops during childhood, adolescence, or young
adulthood.
•
It most commonly occurs in white and South Asian persons and
is rare in African-American persons.
•
The predominant physiologic feature is a defect in insulin
secretion caused by mutations in the glucokinase gene or mutations of
transcription factors that regulate expression of the insulin gene and insulin
production.
•
Most p'ts do not require insulin and can be treated with
OHAs, such as sulfonylureas.
•
Tropical
fibrocalculous DM is a type of DM reported in the tropical areas of Asia,
Africa, and South America.
•
The
clinical syndrome consists of a triad of chronic painful pancreatitis,
malabsorption, and steatorrhea due to pancreatic exocrine insufficiency, along
with DM. Histories frequently include chronic caloric and protein malnutrition.
Pancreatic calculi can be detected in more than 90% of p'ts.
•
Tropical
DM is usually severe and often must be controlled with insulin; however, p'ts
rarely become ketotic after insulin is withdrawn.
Summary
•
Recent evidence indicates that what was once described as
"atypical DM" is a common clinical presentation, affecting 20% to 50%
of African-American and Hispanic p'ts with new diagnoses of DKA.
•
Most p'ts with ketosis-prone type 2 DM are obese,
middle-aged men with a strong family history of type 2 DM.
•
Severe impairment of both insulin secretion and insulin
action are found at presentation, and aggressive diabetic management results in
marked improvement in ß-cell function and insulin sensitivity sufficient to
allow discontinuation of insulin therapy within a few months of treatment.
•
The remission phase is usually less than 2 years when p'ts
are treated with diet alone; however, low-dose sulfonylurea and metformin
therapy may delay the recurrence of hyperglycemia.
•
The pathophysiologic mechanisms involved in its cause are
unknown, but preliminary evidence suggests that p'ts with ketosis-prone type 2
DM have a unique propensity to glucose desensitization.
•
Determination
of autoimmune markers (islet-cell and glutamic acid decarboxylase antibodies)
is useful in excluding p'ts with slow-onset type 1 DM or latent autoimmune DM.
• The presence of positive
autoantibodies and measurement of basal or glucagon-stimulated C-peptide levels
may be useful in predicting near-normoglycemic remission and long-term insulin
dependence in obese p'ts with a history of DKA.
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