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CHAPTER 17
ACUTE METABOLIC
COMPLICATIONS IN DIABETES
Arleta Rewers, MD, PhD
Dr. Arleta Rewers is Associate Professor, Department of Pediatrics at University of Colorado Denver School of Medicine, Aurora, CO.
SUMMARY
Diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia are acute and potentially
life-threatening complications of diabetes. DKA and severe hypoglycemia are more common in type 1 diabetes, while HHS without
ketoacidosis is associated more frequently with type 2 diabetes. In the United States, the SEARCH for Diabetes in Youth study reported
that 29% of patients age 11.10 mmol/L]) also meets criteria for
1 diabetes, particularly at the time of diag- gastrointestinal illness, trauma and stress, DKA. Combination of near-normal glucose
nosis. DKA is less common at diagnosis or pump failure can precipitate DKA. In levels and ketoacidosis (“euglycemic
and during the course of type 2 diabetes. type 2 diabetes patients, DKA occurs ketoacidosis”) has been reported in preg-
during concomitant acute illness or during nant adolescents, very young or partially
DKA is caused by very low levels of effec- transition to insulin dependency. treated children (5), and children fasting
tive circulating insulin and a concomitant during a period of insulin deficiency (6).
increase in counterregulatory hormones DEFINITION
levels, such as glucagon, catecholamines, The American Diabetes Association (1,2), Administrative data sets use International
cortisol, and growth hormone. This the International Society for Pediatric Classification of Diseases, Ninth Revision
combination leads to catabolic changes and Adolescent Diabetes (3), and jointly (ICD-9) or Tenth Revision (ICD-10), codes
in the metabolism of carbohydrates, fat, the European Society for Paediatric to categorize diabetes and diabetic
and protein. Impaired glucose utilization Endocrinology and the Lawson Wilkins complications. The ICD-9 code for DKA
and increased glucose production by the Pediatric Endocrine Society (4) agreed to is 250.1x (250.10–250.13). However, the
liver and kidneys result in hyperglycemia. define DKA as a triad of: code 250.3 (diabetes with other coma) is
Lipolysis leads to increased production used for DKA coma, as well as for coma
of ketones, especially beta-hydroxybu- § hyperglycemia, i.e., plasma glucose caused by severe hypoglycemia. In the
tyrate (β-OHB), ketonemia, and metabolic >250 mg/dL (>13.88 mmol/L) ICD-10 categories for diabetes (E10–E14),
acidosis, which is exaggerated by ongoing § venous pHDIABETES IN AMERICA, 3rd Edition
The incidence of DKA varies with the was found less frequently as the initial first-degree relative with type 1 diabetes,
definition; therefore, it is important to manifestation of diabetes. DKA was shows a protective effect. A similar protec-
standardize criteria for comparative epide- present at diagnosis in 20% of patients in tive effect is observed among children
miologic studies. the Rhode Island Hospital Study, which involved in longitudinal etiological studies.
was population based (24). A community- In addition, medications (glucocorticoids,
PREVALENCE OF DIABETIC based Rochester, Minnesota, study found atypical antipsychotics, and diazoxide)
KETOACIDOSIS AT THE that 23% of diabetes patients presented can contribute to precipitation of DKA in
DIAGNOSIS OF DIABETES with DKA as the initial manifestation. DKA individuals without a previous diabetes
In the United States, the large, popula- was more frequent in patients diagnosed diagnosis (33,34).
tion-based SEARCH for Diabetes in Youth before age 30 years, reaching 26%,
study reported that 29% of patients with and was present in only 15% of those Most episodes of DKA beyond
type 1 diabetes ageAcute Metabolic Complications in Diabetes
to acute complications among diabetic TABLE 17.1. Hospitalizations for Acute Complications of Diabetes, by Age, U.S.,
patients between 2001 and 2010 2001–2010
(Table 17.1) decreased compared to the
AVERAGE ANNUAL PERCENT (SE)
time period 1981–1991 (46), except ACUTE COMPLICATIONS NUMBER OF DISCHARGES OF TOTAL* DIABETES
for an increase in hospitalizations due (ICD-9-CM), BY AGE (YEARS) (THOUSANDS) DISCHARGES
to acidosis. This finding may reflect an Diabetic ketoacidosis (250.1)
increase in the rates of lactic acidosis (LA) All 157.7 3.0 (0.05)
among patients with underlying diabetesDIABETES IN AMERICA, 3rd Edition
TABLE 17.2. Annual Hospitalizations for Diabetic Ketoacidosis and Diabetic Coma, by Age, Sex, and Race, U.S., 2001–2010
DIABETIC KETOACIDOSIS DIABETIC COMA NEC
DIABETES ALL Percent (SE) Percent (SE)
DISCHARGES DISCHARGES* Among All Among All
(NUMBER IN (NUMBER IN Number Diabetes Among All Number Diabetes Among All
CHARACTERISTICS THOUSANDS) THOUSANDS) (Thousands) Discharges Discharges (Thousands) Discharges Discharges
Total 5,180 38,619 157.7 3.0 (0.05) 0.4 (0.01) 7.9 0.2 (0.01) 0.02 (0.002)
Age (years)
30%–40%
2 Relative standard error >40%–50%
3 Estimate is too unreliable to present; ≤1 case or relative standard error >50%.
SOURCE: National Hospital Discharge Surveys 2001–2010
among those without DKA. As DKA is visits for DKA was 64 per 10,000 U.S. polydipsia, polyuria, and polyphagia with
treated primarily in hospital settings, the diabetic patients, and the number of visits weight loss, is the best strategy for early
inpatient expenditures attributed to DKA increased between 1993–1998 (315,000) detection of type 1 diabetes and preven-
accounted for >90% of the total excess and 1999–2003 (438,000) (65). tion of DKA at the time of diagnosis.
medical expenditures attributed to DKA Both public and health professional
(63). Among adults with type 1 diabetes, During 2004, there were 120,000 education should make people aware of
reported medical expenditures are twice admissions due to DKA, 15,000 due to those symptoms, as patients admitted
as high ($13,046 [2007 dollars]), most hyperosmolar hyperglycemic state (HHS), with severe DKA are often seen hours
likely due to coexisting comorbidities (62). and an additional 5,000 due to “diabetic or days earlier by health care providers
Tieder et al. examined a retrospective coma” (66). Based on the Diagnostic who missed the diagnosis, particularly
cohort of children age 2–18 years with Related Group codes in the inpatient in the youngest children (69,70). The
a diagnosis of DKA between 2004 and records, the total hospital cost for DKA Diabetes Autoimmunity Study in the
2009. The mean hospital-level total was estimated at $1.4–$1.8 billion. Young, an observational study following
standardized cost of DKA treatment was An independent analysis by Kitabchi et al. children at genetically high risk for type 1
$7,142 (64). estimated the annual hospital cost of DKA diabetes by periodic testing for diabetes
in the United States in excess of $1 billion autoantibodies, glycosylated hemo-
According to National Hospital Ambulatory (67). Approximately 25% of the cost is globin (A1c), and random blood glucose,
Medical Care Surveys between 1993 and related to DKA at diabetes diagnosis (68). demonstrated that prevention of DKA
2003, DKA accounted for approximately in newly diagnosed children is possible.
753,000 visits or an average 68,000 visits PREVENTION The prevalence of DKA at the time of
per year. The majority of DKA patients Prevention of DKA should be one of diagnosis among children enrolled in this
(87%) were admitted, with most admis- the main goals of diabetes education. study was significantly lower compared
sions to a non-intensive care unit setting. Knowledge of the signs and symptoms to the community level (71). Similar find-
The rate of emergency department of diabetes, such as the classic triad of ings came from the Diabetes Prevention
17–4Acute Metabolic Complications in Diabetes
Trial (72). A community intervention to In adults, in the absence of cardiac compro- administration of an initial intravenous dose
raise awareness of the signs and symp- mise, isotonic saline is given at a rate of of regular insulin (0.1 units/kg) followed
toms of childhood diabetes in the Parma 15–20 mL/kg per hour or 1–1.5 L during by the infusion of 0.1 units/kg per hour.
region of Italy reduced the prevalence of the first hour. Subsequent fluid replace- A prospective randomized study reported
DKA at diagnosis of type 1 diabetes from ment depends on hemodynamic status, that a bolus dose of insulin is not necessary,
83% to 13% (73). The effect persisted 8 serum electrolyte levels, and urinary output. if patients receive an hourly insulin infusion
years later, but there was an indication Treatment algorithms recommend the of 0.14 units/kg body weight (82).
that the campaign should be periodically
renewed (74).
FIGURE 17.1. Trends in Age-Standardized Mortality Rate Coded to Diabetic Ketoacidosis
Per 100,000 People With Diabetes, U.S., 2000–2009
Most studies have shown that most
episodes of DKA beyond disease Underlying cause* Multiple causes†
diagnosis are preventable by identification 25
of at-risk patients and use of targeted
Mortality rate (per 100,000)
interventions. Comprehensive diabetes 20
programs and telephone help lines
reduced the rates of DKA from 15–60 15
to 5–6 per 100 patient-years (75,76,77).
10
In the adolescent cohort of the Diabetes
Control and Complications Trial (DCCT), 5
intensive diabetes management was
associated with less DKA (conventional 0
and intensive treatment groups: 4.7 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Year
and 2.8 episodes per 100 patient-years,
respectively) (78). In patients treated with Ketoacidosis is defined as International Classification of Diseases, Tenth Revision (ICD-10), codes E10.1, E11.1,
insulin pumps, episodes of DKA can be E12.1, E13.1, or E14.1. Data are standardized to the National Health Interview Survey 2010 diabetes population
using age categoriesDIABETES IN AMERICA, 3rd Edition
HYPERGLYCEMIC HYPEROSMOLAR STATE
PATHOGENESIS disease, and cancer, seems to be respon- controls) to be independently associated
Decrease in the effective action of circu- sible for the higher mortality associated with the presence of HHS (95). Among
lating insulin coupled with a concomitant with HHS compared to DKA (86). 200 HHS patients in Rhode Island,
elevation of counterregulatory hormones nursing home residents accounted for
is the underlying mechanism for both The incidence of HHS is most likely under- 18% of the cases (85).
HHS and DKA. These alterations lead estimated in children, as the presenting
to increased hepatic and renal glucose clinical picture in many patients has MORBIDITY AND MORTALITY
production and impaired glucose utiliza- elements of both HHS and DKA (87,88). Hospitalization data from the National
tion in peripheral tissues, which result in Hospital Discharge Surveys 2001–2010
hyperglycemia and parallel changes in Several studies of pediatric and were analyzed for Diabetes in America,
osmolality of the extracellular space (83). adolescent diabetic patients, mostly case confirming that HHS occurs rarely (Tables
HHS is associated with glycosuria, leading series or single-institution reviews, have 17.1 and 17.3). The 18–44 years age group
to osmotic diuresis, with loss of water, described more than 50 cases of HHS had the highest percentage of hospital-
sodium, potassium, and other electrolytes. (7,89,90,91,92). Most patients were izations listing HHS. The average annual
In HHS, insulin levels are inadequate for adolescents with newly diagnosed type number of hospital discharges listing HHS
glucose utilization by insulin sensitive 2 diabetes, and many were of African as a cause doubled to 23,900 during 2001–
tissues but sufficient (as determined by American descent. A study based on 2010 compared to 10,800 in 1989–1991.
residual C-peptide) to prevent lipolysis data from the Kid’s Inpatient Database
and ketogenesis (83). provided the first national estimate of In adults, mortality rates attributed to
hospitalizations due to HHS among HHS range from 5% to 25% (82,85,86,
DEFINITION U.S. children between 1997 and 2009. 94,96). The mortality increases sharply
HHS is defined as extreme elevation in blood The estimated population rate for HHS with age from none in patients age 600 mg/dL (>33.30 mmol/L) diagnoses for children age 0–18 years years to 1.2% in those age 35–55 years
and serum osmolality >320 mOsm/kg was 2.1 per 1,000,000 children in 1997, and 15.0% in patients age >55 years.
in the absence of significant ketosis and rising to 3.2 in 2009. The majority (70.5%) A U.S. study of 613 adult patients hospi-
acidosis. Small amounts of ketones may of HHS hospitalizations occurred among talized for hyperglycemic crises reported
be present in blood and urine (84). children with type 1 diabetes (93). similar findings (85). Fatality rates for DKA,
mixed DKA-HHS, and isolated HHS alone
In the ICD-9, the HHS code is 250.2: RISK FACTORS were, respectively, 4%, 9%, and 12%. In
diabetes with hyperosmolarity or hyper- The majority of HHS episodes are precip- both studies, older age and the degree of
osmolar (nonketotic) coma. The ICD-10 itated by an infectious process; other hyperosmolarity were the most powerful
does not have a specific code for HHS; precipitants include cerebrovascular predictors of a fatal outcome. Deaths
E1x.0 denotes coma with or without keto- accident, alcohol abuse, pancreatitis, due to hyperglycemic crisis in adults with
acidosis, hyperosmolar or hypoglycemic myocardial infarction, trauma, and diabetes dropped from 2,989 in 1985 to
(x digit is used to define type of diabetes). drugs. In a case series of 119 patients 2,459 in 2002, according to data from the
with HHS, nearly 60% of the patients National Vital Statistics System. During
INCIDENCE AND PREVALENCE had an infection, and 42% had a stroke the time period, age-adjusted death rates
The incidence of HHS is unknown because (94). Medications affecting carbohydrate decreased from 42 to 24 per 100,000
of the lack of population-based studies metabolism, such as corticosteroids, adults with diabetes (97); the decrease
and multiple comorbidities often found in thiazides, and sympathomimetic agents was found in all age groups (Figure 17.3)
these patients. Estimated rates of hospital (e.g., dobutamine and terbutaline), may (97). During the period between 1997 and
admissions for HHS are lower compared also precipitate the development of HHS. 2009, the mortality rate among children
to DKA. HHS accounts forAcute Metabolic Complications in Diabetes
TABLE 17.3. Annual Hospitalizations for Diabetic Hyperosmolar Nonketotic Coma, by Age, PREVENTION AND TREATMENT
Sex, and Race, U.S., 2001–2010 Appropriate diabetes education, adequate
treatment, and frequent self-monitoring
PERCENT (STANDARD ERROR)
DIABETIC HYPEROSMOLAR of blood glucose help to prevent HHS
NONKETOTIC COMA Among Diabetes Among All
CHARACTERISTICS (NUMBER IN THOUSANDS) Discharges Discharges* in patients with known diabetes. HHS
can be precipitated by dehydration and
Total 23.9 0.5 (0.02) 0.06 (0.003)
medications, such as corticosteroids,
Age (years) thiazides, and sympathomimetic agents.
40%–50%
3 Estimate is too unreliable to present; ≤1 case or relative standard error >50%.
SOURCE: National Hospital Discharge Surveys 2001–2010
FIGURE 17.3. Age-Specific Death Rates for Hyperglycemic Crisis Among Persons With
Diabetes Age ≥18 Years, by Age, U.S., 1985–2002
18–44 years 45–64 years ≥65 years
90
80
Death rate (per 100,000 people with diabetes)
70
60
50
40
30
20
10
0
86 01
85
00
90
99
93
94
92
98
89
02
88
95
96
97
87
91
19 20
19
19
19
19
19
19
20
19
19
19
19
20
19
19
19
19
Year
Data are based on the National Vital Statistics System 1985–2002. Denominators are based on National Health
Interview Surveys 1985–2002 data.
SOURCE: Reference 97, copyright © 2006 American Diabetes Association, reprinted with permission from The
American Diabetes Association
17–7DIABETES IN AMERICA, 3rd Edition
LACTIC ACIDOSIS
DEFINITION The frequency of hospitalizations due to comparative trials and observational
LA consists of elevation of lactic acid LA increased from 0.6% to 1.2% among cohort studies showed no difference in
above 5.0 mEq/L with acidosis (pH 0.4–45 years, in women, in whites, and contraindicated in conditions associated MORBIDITY AND MORTALITY
in patients for whom diabetes was not with LA, such as cardiovascular, renal, LA leads to neurologic impairment. Rapid
listed on the hospital discharge summary, hepatic, and pulmonary diseases, and correction of the acid-base and electro-
the percentage of diabetes discharges advanced age. However, a Cochrane lyte disturbances may induce cerebral
with LA was greater in younger people. Database review of prospective edema. The mechanism of cerebral
TABLE 17.4. Annual Hospitalizations for Lactic Acidosis, by Diabetes Status, Age, Sex, and Race, U.S., 2001–2010
DIABETES NO DIABETES
Lactic Acidosis Percent (SE) Lactic Acidosis Percent (SE)
and Diabetes Among Diabetes Among All and No Diabetes Among All
CHARACTERISTICS (Number in Thousands) Discharges Discharges* (Number in Thousands) Discharges
Total 65.2 1.2 (0.03) 0.17 (0.005) 340.3 1.02 (0.012)
Age (years)
30%–40%
SOURCE: National Hospital Discharge Surveys 2001–2010
17–8Acute Metabolic Complications in Diabetes
edema in the course of LA is unclear. PREVENTION AND TREATMENT The only effective treatment for LA is
The mortality rates from LA are high and LA is usually associated with unexpected cessation of lactic acid production by
associated with higher lactic acid levels. and catastrophic hypoxic events and is the improvement of tissue oxygenation.
Based on data from National Hospital therefore less likely to be amenable to Treatment of underlying conditions,
Discharge Surveys 2001–2010, LA preventive measures. Long-term preven- such as shock or myocardial infarc-
accounts for 1.2% of all hospitalizations tion of cardiovascular disease or sepsis tion, includes restoration of the fluid
in diabetic patients (Table 17.4). among diabetic patients through improved volume, improvement of cardiac function,
glucose control and alteration of other risk amelioration of sepsis, and correction of
factors could decrease the incidence of LA. hyperglycemia (104).
HYPOGLYCEMIA
PATHOGENESIS DEFINITION The DCCT defined severe hypoglycemia as
Hypoglycemia is the most common, Various definitions of hypoglycemia are in an episode in which the patient required
life-threatening acute complication of use; for comparative epidemiologic studies, assistance with treatment from another
diabetes treatment. It is characterized by it is important to standardize criteria. The person to recover; blood glucose level had
multiple risk factors and complex patho- American Diabetes Association Workgroup to be documented asDIABETES IN AMERICA, 3rd Edition INCIDENCE IN TYPE 1 agents. However, the risk of hypoglycemia based on whether they were receiving DIABETES PATIENTS increases with transition to insulin- insulin and/or sulfonylureas. Instances of The incidence of moderate or mild hypo- dependence. In the United Kingdom overtreatment were defined as using one glycemia is unknown; those events are Prospective Diabetes Study (UKPDS), of these agents in patients with A1c levels frequent among patients treated with the risk of severe hypoglycemia was 1.0 below specific thresholds, such as
Acute Metabolic Complications in Diabetes
uptake, which may result in hypoglycemia psychiatric disorders affecting patients and 30% of patients with type 1 diabetes,
without modification of insulin dose and their families have been shown to have increase the risk of hypoglycemia
intake of carbohydrates (151). significant influence on glycemic control (162,163,164,165). In pregnancy with
and the rate of hypoglycemia. Family type 1 diabetes, the incidence of mild and
Alcohol consumption is a significant relationships and personality type have severe hypoglycemia is highest in early
risk factor for development of severe also had a significant effect on adaptation pregnancy, although metabolic control
hypoglycemia. Alcohol suppresses to illness and metabolic control among is usually tighter in the last part of preg-
gluconeogenesis and glycogenolysis persons with diabetes (156). Presence of nancy. Predictors for severe hypoglycemia
and acutely improves insulin sensitivity psychiatric disorders has a detrimental are history of severe hypoglycemia and
(152,153) and may induce hypoglycemia effect on metabolic control (157,158) impaired awareness (166). Chronic kidney
unawareness (154). In combination and compliance with treatment (159). disease can be found in up to 23% of
with exercise, drinking alcohol can lead Prevalence of psychiatric disorders among patients with diabetes. Chronic kidney
to severe hypoglycemia with a delay patients with type 1 diabetes reached 48% disease is an independent risk factor for
of symptoms up to 10–12 hours after by 10 years of diabetes duration and age hypoglycemia and augments the risk
alcohol consumption (155). 20 years in a small longitudinal cohort already present in people with diabetes
(160,161), the most prevalent being major (167,168).
Family dynamics, behavioral factors, and depressive disorder (28%). Prevalence of
psychiatric factors are important risk psychiatric disorders, however, has been MORBIDITY AND MORTALITY
factors, particularly in the pediatric popula- shown to be much lower in other studies, A new analysis for Diabetes in America
tion. The DCCT showed that conventional as discussed in Chapter 33 Psychiatric and of the frequency of hypoglycemia
risk factors explained only 8.5% of the Psychosocial Issues Among Individuals (ICD-9 codes 250.8 and 251.2) as a
variance in the occurrence of severe hypo- Living With Diabetes. discharge diagnosis for hospitalizations
glycemia (117). Factors such as inadequate in the United States in 2001–2010 is
diabetes education, low socioeconomic Coexisting autoimmune conditions, such shown in Tables 17.1 and 17.5, using data
status, lack of insurance, unstable living as autoimmune thyroid, celiac, and from the National Hospital Discharge
conditions, behavioral factors, and Addison’s diseases, occurring in up to Survey. Hypoglycemia was listed as
TABLE 17.5. Annual Hospitalizations for Hypoglycemia, by Diabetes Status, Age, Sex, and Race, U.S., 2001–2010
DIABETES NO DIABETES
Hypoglycemia Percent (SE) Hypoglycemia Percent (SE)
and Diabetes Among All Diabetes Among All With No Diabetes Among All
CHARACTERISTICS (Number in Thousands) Discharges Discharges* (Number in Thousands) Discharges
Total 287.6 5.4 (0.07) 0.74 (0.009) 28.9 0.09 (0.003)
Age (years)
50%).
AI/AN, American Indian/Alaska Native; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.
* All discharges include patients with diabetes and those without diabetes.
† Twenty-three percent of participants were missing race data.
1 Relative standard error >30%–40%
2 Relative standard error >40%–50%
SOURCE: National Hospital Discharge Surveys 2001–2010
17–11DIABETES IN AMERICA, 3rd Edition an underlying cause in about 288,000 baseline), while increasing the incidence of lower A1c levels and improve quality of hospitalizations, which represented hypoglycemia, did not lead to a significant life compared to multiple daily injections 5.4% of hospitalizations due to diabetes. worsening of neuropsychological or cogni- of insulin and, of importance, reduce the Hospital discharges for hypoglycemia in tive functioning during the trial (186,187), rate of severe hypoglycemia (193,194). diabetic patients occurred least often in as well as 18 years after entry into the patients age
Acute Metabolic Complications in Diabetes
diabetes management is the development Behavioral Interventions accomplished by giving glucose tablets or
of automatic glucose sensing and insulin Behavioral interventions, including sweetened fluids, such as juice, glucagon
delivery without patient intervention (206). intensive diabetes education, good injection in unconscious patients, or
Studies evaluating closed-loop insulin access to care, and psychosocial dextrose infusion in a hospital setting.
delivery suggest improved glucose control support, including treatment of
and a decreased risk of hypoglycemia psychiatric disorders, lower the risk of
(207,208). Data from the Automation to hypoglycemia (210,211).
Simulate Pancreatic Insulin REsponse
(ASPIRE) study confirmed that use of TREATMENT
sensor-augmented insulin pump therapy The goal of treatment of hypogly-
with the threshold-suspend feature cemia is to immediately increase the
reduced nocturnal hypoglycemia, without blood glucose approximately 3–4
increasing A1c values (209). mmol/L (~55–70 mg/dL). This can be
LIST OF ABBREVIATIONS CONVERSIONS
A1c. . . . . . . . . . . . . . . . . . . glycosylated hemoglobin Conversions for A1c and glucose
β-OHB . . . . . . . . . . . . . . . . beta-hydroxybutyrate values are provided in Diabetes in
CSII . . . . . . . . . . . . . . . . . .continuous subcutaneous insulin infusion America Appendix 1 Conversions.
DCCT . . . . . . . . . . . . . . . . . Diabetes Control and Complications Trial
DKA . . . . . . . . . . . . . . . . . . diabetic ketoacidosis
HHS . . . . . . . . . . . . . . . . . . hyperglycemic hyperosmolar state
ICD-9-CM/ICD-10 . . . . . . . International Classification of Diseases, Ninth Revision, DUALITY OF INTEREST
Clinical Modification/Tenth Revision
Dr. Rewers reported no conflicts of
LA . . . . . . . . . . . . . . . . . . .lactic acidosis
interest.
SEARCH . . . . . . . . . . . . . .SEARCH for Diabetes in Youth study
UKPDS. . . . . . . . . . . . . . . .United Kingdom Prospective Diabetes Study
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