8/12/2019 Hyperglycemic Crises in Pa
1/55
Hyperglycemic Crises in Patients
With Diabetes Mellitus
dr. Tjatur Winarsanto SpPD
8/12/2019 Hyperglycemic Crises in Pa
2/55
H
Introduction
Ketoacidosisand hyperosmolar hyperglycemiaare the
two most serious acute metabolic complications ofdiabetes, even if managed properly.
They can occur in both type 1 and type 2 diabetes.
Mortality ratein DKA is
8/12/2019 Hyperglycemic Crises in Pa
3/55
H
PATHOGENESIS(1)
Pathogenesis of DKA is better understood than that of HHS,
the basic underlying mechanism for both disorders is areduction in net effective action of circulating insulincoupled
with a concomitant elevation of counterregulatory hormones,
such as glucagon, catecholamines, cortisol, and growth
hormone. These hormonal alterations in DKA and HHS lead to
increased hepatic and renal glucose productionand impaired
glucose utilization inperipheral tissues, which result in
hyperglycemiaand parallel changes in osmolality of theextracellular space.
8/12/2019 Hyperglycemic Crises in Pa
4/55
H
PATHOGENESIS(2)
The combination of insulin deficiency and increased
counterregulatory hormones in DKAalso leads to releaseof free fatty acidsinto the circulation from adipose tissue(lipolysis) and to unrestrained hepatic fatty acid oxidationto ketone bodies(-hydroxybutyrate [-OHB] andacetoacetate), with resulting ketonemiaand metabolicacidosis.
HHS may be due to plasma insulin concentrationinadequate to facilitate glucose utilization by insulin-
sensitive tissues but adequate (as determined by residual peptide) toprevent lipolysis and subsequent ketogenesis,although the evidence for this is weak.
8/12/2019 Hyperglycemic Crises in Pa
5/55
H
PATHOGENESIS(3)
Both DKA and HHS are associated with
glycosuria, leading to osmotic diuresiswith loss
of water, sodium, potassium, and other
electrolytes.
The laboratory and clinical characteristics ofDKA and HHS are summarized in Tables 1 and 2.
As can be seen, DKA and HHS differ in
magnitude of dehydrationand degree of ketosis
(and acidosis).
8/12/2019 Hyperglycemic Crises in Pa
6/55
H
PRECIPITATING FACTORS (1)
The most common in development of DKA or HHS isinfection. Others include CVA, alcohol abuse,
pancreatitis, MI, trauma, and drugs.
Newly onset type 1 diabetes or discontinuation orinadequate insulin in established type 1 diabetescommonly leads to DKA.
Elderly individualswith newly onset diabetes(particularly residents of chronic care facilities) orindividuals with known diabetes who become
hyperglycemic and are unaware of it or are unable to tafluidswhen necessary are at risk forHHS.
8/12/2019 Hyperglycemic Crises in Pa
7/55
H
PRECIPITATING FACTORS (2)
Drugs that affect carbohydrate metabolism, such as
corticosteroids, thiazides, and sympathomimetic agents(e.g., dobutamine and terbutaline), may precipitate thedevelopment of HHS or DKA.
In young type 1 diabetes,psychologicalproblems
complicated by eating disordersmay be a contributingfactor in 20%of recurrent ketoacidosis.
Factors that may lead to insulin omissionin youngerpts include fear of weight gain with improved
metabolic control, fear of hypoglycemia, rebellion fromauthority, and stress of chronic disease.
8/12/2019 Hyperglycemic Crises in Pa
8/55
H
DIAGNOSIS-History and physical examination (1)
The process of HHS usually evolves over several days
to weeks, whereas the evolution of acute DKA
episode in type 1 diabetes or even in type 2 diabetes
tends to be much shorter.
Although the symptoms of poorly controlled diabetesmay be present for several days, the metabolic
alterations typical of ketoacidosisusually evolve
within a short time frame (typically
8/12/2019 Hyperglycemic Crises in Pa
9/55
H
DIAGNOSIS-History and physical examination (2)
Occasionally, the entire symptomatic presentation may
evolve or develop more acutely, and the pt maypresent in DKA with no prior clues or symptoms.
For both DKA and HHS, the classical clinical picture
includes polyuria, polydipsia, polyphagia, weight loss,
vomiting, abdominal pain (only in DKA), dehydration,
weakness, clouding of sensoria, and finally coma.
8/12/2019 Hyperglycemic Crises in Pa
10/55
H
DIAGNOSIS-History and physical examination (3)
Physical findingsmay include poor skin turgor, Kussma
respirations (in DKA), tachycardia, hypotension,alteration in mental status, shock, and ultimately coma
(more frequent in HHS).
Up to 25%of DKA haveemesis, which may be coffee-
ground in appearance and guaiac positive. Endoscopy h
related this finding to presence of hemorrhagic gastritis
Mental statuscan vary from full alertness to profound
lethargy or coma, with the latter more frequent in HHS.
8/12/2019 Hyperglycemic Crises in Pa
11/55
H
DIAGNOSIS-History and physical examination (4)
Althoughinfectionis a common precipitating factor for
both DKA and HHS, pts can be normothermic or even
hypothermic primarily because ofperipheral vasodilation
Hypothermia is a poor prognostic sign.
Caution when abdominal painon presentation, could be
either a result or a cause (particularly in younger) of DKAFurther evaluation is necessary if this complaint does not
resolve with resolution of dehydration and metabolic
acidosis.
8/12/2019 Hyperglycemic Crises in Pa
12/55
H
DIAGNOSIS-Laboratory findings (1)
Initial laboratory evaluation of suspected DKA or HHS
should include determination of plasma glucose, BUN/Crserum ketones, electrolytes (with calculated anion gap),
osmolality, urinalysis, urine ketones by dipstick, as well a
initial ABG, CBC/DC, and ECG.
Bacterial culturesof urine, blood, and throat, etc., should
obtained and appropriate antibiotics given if infection is
suspected.
8/12/2019 Hyperglycemic Crises in Pa
13/55
H
DIAGNOSIS-Laboratory findings (2)
HbA1cmay be useful in determining whether this acute
episode is the culmination of an evolutionary process
in previously undiagnosed or poorly controlled
diabetes or a truly acute episode in an otherwise well-
controlled p
t. CXRshould also be obtained if indicated. Tables 1 and
2depict typical laboratory findings in DKA or HHS.
8/12/2019 Hyperglycemic Crises in Pa
14/55
H
DIAGNOSIS-Laboratory findings (3)
The majority of hyperglycemic emergencies present with
leukocytosisproportional toblood ketone bodyconcentration.
Serum sodiumis usually decreasedbecause of the osmotiflux of water from intracellular to extracellular space in th
presence of hyperglycemia, and less commonly, serumsodium may be falsely lowered by severehypertriglyceridemia.
Serumpotassiummay be elevatedbecause of an
extracellular shift of potassium caused by insulindeficiency, hypertonicity, and acidemia.
8/12/2019 Hyperglycemic Crises in Pa
15/55
H
DIAGNOSIS-Laboratory findings (4)
Pts with low-normal or low serum potassium onadmission have severe total-body potassium deficiency anrequire very careful cardiac monitoring and more vigorou
potassium replacement, because treatment lowerspotassium further and can provoke cardiac dysrhythmia.
The occurrence of stupor or coma in diabetic p
ts in theabsence of definitive elevation of effective osmolality(>320 mOsm/kg) demands immediate consideration ofother causes of mental status change.
Effective osmolalitymay be calculated by the followingformula: 2[measured Na (mEq/l)]glucose (mg/dl)/18.
8/12/2019 Hyperglycemic Crises in Pa
16/55
H
DIAGNOSIS-Laboratory findings (5)
Amylaselevels are elevated in the majority of DKA,
but this may be due to nonpancreatic sources, such astheparotid gland.
Serum lipase determination may be beneficial in the
D/D of pancreatitis. However, lipase could also beelevated in DKA.
Abdominal pain and elevation of serum amylase and
liver enzymes are noted more commonly in DKA than
in HHS.
Diff i l di i (1)
8/12/2019 Hyperglycemic Crises in Pa
17/55
H
Differential diagnosis (1)
Not all pts with ketoacidosis have DKA.
Starvation ketosis and alcoholic ketoacidosis (AKA)aredistinguished by clinical history and by plasma glucose thatrange from mildly elevated (rarely >250 mg/dl) tohypoglycemia. Although AKA can result in profound acidosis,the serum bicarbonate in starvation ketosis is usually not lower
than 18 mEq/l. DKA must also be distinguished from other causes of high AG
metabolic acidosis, including lactic acidosis, ingestion of drugssuch as salicylate, methanol, ethylene glycol, and paraldehyde,and CRF (which is more typically hyperchloremic acidosisrather than high AG acidosis).
8/12/2019 Hyperglycemic Crises in Pa
18/55
H
Differential diagnosis (2)
Clinical historyof previous drug intoxications or metformin
use should be sought. Measurement of blood lactate, serumsalicylate, and blood methanol level can be helpful in thesesituations.
Ethylene glycol (antifreeze)is suggested by presence ofcalcium oxalate and hippurate crystals in the urine.
Paraldehyde ingestionis indicated by its characteristic strongodor on the breath.
Because these intoxicants are low molecular weight organiccompounds, they can produce an osmolar gap in addition to
AG acidosis
8/12/2019 Hyperglycemic Crises in Pa
19/55
H
TREATMENT
Successful treatment of DKA and HHS requirescorrection of dehydration, hyperglycemia, and
electrolyte imbalances; identification of comorbid
precipitating events; and above all, frequent pt
monitoring. Guidelines for management of pts with DKA and
HHS follow and are summarized in Figs. 1, 2, and 3.
Table 3includes a summary of major recommendationsand evidence gradings.
8/12/2019 Hyperglycemic Crises in Pa
20/55
H
Fluid therapy- Adult patients (1)
Initial fluid therapy is directed toward expansion of theintravascular and extravascular volume and restoration o
renal perfusion.
In the absence of cardiac compromise, isotonic saline
(0.9% NaCl)is infused at a rate of 1520ml/kgw/h orgreater during 1st hour (~11.5 liters in average adult).
Subsequent choice for fluid replacement depends on sta
of hydration, serum electrolyte levels, and urinary outpu
8/12/2019 Hyperglycemic Crises in Pa
21/55
H
Fluid therapy- Adult patients (2)
In general, 0.45% NaClinfused at 414 ml/kg/h isappropriate if the corrected serum sodium is normal or
elevated.
0.9% NaClat a similar rate is appropriate if corrected
serum sodium is low. Once renal function is assured, the infusion should
include 2030mEq/l potassium (2/3 KCl and 1/3
KPO4) until pt is stable and can tolerate oral
supplementation.
8/12/2019 Hyperglycemic Crises in Pa
22/55
H
Fluid therapy- Adult patients (3) Successful progress with fluid replacement is judged by
hemodynamic monitoring (improvement in BP),measurement of fluid input/output, and clinical
examination.
Fluid replacement should correct estimated deficits
within first 24 h. The induced change in serumosmolality should not exceed 3 mOsm/kg/H2O/h.
In pts with renal or cardiac compromise, monitoring
of serum osmolality and frequent assessment of cardiacrenal, and mental status must be performed during fluid
resuscitation to avoid iatrogenic fluid overload.
Fluid therapy- Pediatric patients (
8/12/2019 Hyperglycemic Crises in Pa
23/55
H
Fluid therapy- Pediatric patients (
8/12/2019 Hyperglycemic Crises in Pa
24/55
H
Fluid therapy- Pediatric patients (
8/12/2019 Hyperglycemic Crises in Pa
25/55
H
Fluid therapy Pediatric patients (
8/12/2019 Hyperglycemic Crises in Pa
26/55
H
Insulin therapy (1)
Unless the episode of DKA is mild (Table 1), RI by
continuous intravenous infusion is treatment of choice. Once hypokalemia (K+
8/12/2019 Hyperglycemic Crises in Pa
27/55
H
Insulin therapy (2)
If plasma glucose does not fall by 50 mg/dlfrom initiavalue in 1st hour, check hydration status; if acceptable
insulin infusion may be doubled every hour until asteady glucose decline between 50 and 75mg/h.
When plasma glucose reaches 250 mg/dl in DKAor300 mg/dl in HHS, it may be possible to decrease
insulin infusion rate to 0.050.1U/kg/h (36 U/h), anddextrose (510%)may be added to IV fluids.
Thereafter, insulin administration rate or concentrationof dextrose may need to be adjusted to maintain theabove glucose values until acidosis in DKA or mentalobtundation and hyperosmolarity in HHS are resolved.
Insulin therapy (3)
8/12/2019 Hyperglycemic Crises in Pa
28/55
H
Insulin therapy (3)
Ketonemiatypically takes longer to clear thanhyperglycemia.
The nitroprusside methodonly measures acetoaceticacid and acetone. However, -OHB, the strongest andmost prevalent acid in DKA, is not measured by thenitroprusside method.
During therapy, -OHB is converted to acetoacetic acidwhich may lead the clinician to believe that ketosis hasworsened. Therefore, assessments of urinary or serumketone levels by nitroprusside method should notbeused as an indicator of response to therapy.
Insulin therapy (4)
8/12/2019 Hyperglycemic Crises in Pa
29/55
H
Insulin therapy (4)
During therapy for DKA or HHS, blood should be
drawn every 24 hfor determination of serum
electrolytes, glucose, BUN, Cr, osmolality, and
venous pH(for DKA).
Generally, repeat ABGs are unnecessary; venous pH(which is usually 0.03 Ulower than arterial pH) and
anion gap can be followed to monitor resolution of
acidosis.
Insulin therapy (5)
8/12/2019 Hyperglycemic Crises in Pa
30/55
H
Insulin therapy (5)
With mild DKA, RI given subcutaneously or
intramuscularly every hour is as effective asintravenous administration in lowering bloodglucose and ketone bodies.
Mild DKA should first receive a "priming" dose of
RI of 0.40.6 U/kgw, half as an intravenous bolusand half as a subcutaneous or intramuscularinjection.
Thereafter, 0.1U/kg/h of RI should be given
subcutaneously or intramuscularly.
Insulin therapy (6)
8/12/2019 Hyperglycemic Crises in Pa
31/55
H
Insulin therapy (6)
After resolution of DKA (glucose 18 mEq/l, venous pH >7.3, anion gap
8/12/2019 Hyperglycemic Crises in Pa
32/55
H
Potassium (1)
Despite total-body potassium depletion, mild to
moderate hyperkalemiais not uncommon in pts withhyperglycemic crises. Insulin therapy, correction of
acidosis, and volume expansion decrease serum
potassium concentration.
To prevent hypokalemia, potassium replacement is
initiated after serum levels fall below 5.5 mEq/l,
assuming the presence of adequate urine output.
Potassium (2)
8/12/2019 Hyperglycemic Crises in Pa
33/55
H
( )
Generally, 2030 mEqpotassium (2/3 KCl and 1/3
KPO4) in each liter of infusion fluid is sufficient to
maintain a serum potassium concentration within the
normal range of 45 mEq/l.
Rarely, DKA pts may present with significant
hypokalemia. In such cases, potassium replacementshould begin with fluid therapy, and insulin treatment
should be delayed until potassium concentration is
restored to >3.3 mEq/lto avoid arrhythmias or cardiac
arrest and respiratory muscle weakness.
Bicarbonate (1)
8/12/2019 Hyperglycemic Crises in Pa
34/55
H
( ) Bicarbonate use in DKA remains controversial. At a
pH >7.0, reestablishing insulin activity blocks
lipolysis and resolves ketoacidosis without any addedbicarbonate. Prospective randomized studies have
failed to show either beneficial or deleterious changes
in morbidity or mortality with bicarbonate therapy in
DKA with pH between 6.9 and 7.1.
No prospective randomized studies concerning the use
of bicarbonate in DKA with pH values
8/12/2019 Hyperglycemic Crises in Pa
35/55
H
Bicarbonate (2)
Given that severe acidosis may lead to a myriad of
adverse vascular effects, it seems prudent that for adultpts with apH 7.0.
Bicarbonate (3)
8/12/2019 Hyperglycemic Crises in Pa
36/55
H
Bicarbonate (3)
In the pediatric pt, there are no randomized studies in
pts with pH 7.0.
Bicarbonate (4)
8/12/2019 Hyperglycemic Crises in Pa
37/55
H
( )
Insulin, as well as bicarbonate therapy, lowers serum
potassium; therefore, potassium supplementation shouldbe maintained in intravenous fluid as described above a
carefully monitored. (See Fig. 1for guidelines.)
Thereafter, venous pHshould be assessed every 2 h unt
the pH rises to 7.0, and treatment should be repeatedevery 2 h if necessary. (See Kitabchi et al. for a comple
description of studies done to date on the use of
bicarbonate in DKA.)
Phosphate (1)
8/12/2019 Hyperglycemic Crises in Pa
38/55
H
p ( )
Despite whole-body phosphate deficits in DKA that
average ~1.0 mmol/kgw, serum phosphate is oftennormal or increased at presentation.
Phosphate concentration decreases with insulin therapy
Prospective randomized studies have failed to show
any beneficial effect of phosphate replacement on theclinical outcome in DKA, and overzealous phosphate
therapycan cause severe hypocalcemiawith no
evidence of tetany
Phosphate (2)
8/12/2019 Hyperglycemic Crises in Pa
39/55
H
p ( )
To avoid cardiac and skeletal muscle weakness and
respiratory depression due to hypophosphatemia, carefuphosphate replacement may sometimes be indicated incardiac dysfunction, anemia, or respiratory depressionand those serum phosphate
8/12/2019 Hyperglycemic Crises in Pa
40/55
H
Hypoglycemia and hypokalemia
Hyperglycemia
Hyperchloremic metabolic acidosis
Cerebral edema
Adult respiratory distress syndrome
COMPLICATIONS (1)
8/12/2019 Hyperglycemic Crises in Pa
41/55
H
The most common complications of DKA and HHS
include hypoglycemiadue to overzealous treatmentwith insulin, hypokalemia due to insulin
administration and treatment of acidosis with
bicarbonate, and hyperglycemiasecondary to
interruption/discontinuance of intravenous insulintherapy after recovery without subsequent coverage
with subcutaneous insulin.
COMPLICATIONS (2)
8/12/2019 Hyperglycemic Crises in Pa
42/55
H
( )
Commonly, pts recovering from DKA develop
hyperchloremiacaused by the use of excessive saline ffluid and electrolyte replacement and transient non
Anion gap metabolic acidosisas chloride from
intravenous fluids replaces ketoanions lost as sodium
and potassium salts during osmotic diuresis. These biochemical abnormalities are transient and are
not clinically significant except in cases of acute renal
failure or extreme oliguria.
COMPLICATIONS (3)
8/12/2019 Hyperglycemic Crises in Pa
43/55
H
( )
Cerebral edemais a rare but frequently fatal complication
of DKA, occurring in 0.71.0%of children with DKA. Itmost common in children with newly diagnosed diabetes
but has been reported in children with known diabetes an
in young people in their twenties.
Fatal cases of cerebral edema have also been reported witHHS. Clinically, cerebral edema is characterized by a
deterioration in the level of consciousness, with lethargy,
decrease in arousal, and headache.
COMPLICATIONS (4)
8/12/2019 Hyperglycemic Crises in Pa
44/55
H
( )
Neurological deterioration may be rapid, with seizures,
incontinence, pupillary changes, bradycardia, andrespiratory arrest.
These symptoms progress asbrain stem herniation
occurs, may be so rapid that papilledema is not found.
Once clinical symptoms other than lethargy and
behavioral changes occur, mortality is high (>70%),
with only 714%pts recovering without permanent
morbidity.
COMPLICATIONS (5)
8/12/2019 Hyperglycemic Crises in Pa
45/55
H
Although mechanism of cerebral edema is not known, it
likely results from osmotically driven movement of waterinto CNS when plasma osmolality declines too rapidly w
treatment of DKA or HHS.
Lack of information on morbidity associated with cerebra
edema in adult pts; therefore, any recommendations for
adult pts are clinical judgments, rather than scientific
evidence.
COMPLICATIONS (6)
8/12/2019 Hyperglycemic Crises in Pa
46/55
H
Prevention measures that might decrease risk of cerebral
edema in high-risk pts are gradual replacement of
sodium and water deficits in pts who are hyperosmolar(maximal reduction in osmolality3mOsm/kg/H2O/h) and
the addition of dextrose to hydrating solution once blood
glucose reaches 250 mg/dl.
In HHS, a glucose level of 250300mg/dl should be
maintained until hyperosmolarity and mental status
improves and pt becomes clinically stable.
COMPLICATIONS (7)
8/12/2019 Hyperglycemic Crises in Pa
47/55
H
Hypoxemiaand, rarely, noncardiogenic pulmonary edem
may complicate the treatment of DKA. Hypoxemia is
attributed to a reduction in colloid osmotic pressure that
results in increased lung water content and decreased lung
compliance.
DKAwho have a widenedalveolo-arteriolar oxygengradient noted on initial blood gas measurement or with
pulmonaryraleson physical examination appear to be at
higher risk for the development ofpulmonary edema.
Clues To Complications In DKA (1)
8/12/2019 Hyperglycemic Crises in Pa
48/55
H
ComplicationAcute gastric dilatation or
erosive gastritis
Cerebral edema
Hyperkalemia
Hypoglycemia
Hypokalemia
Infection
CluesVomiting of blood or coffee-grou
material
Obtundation or coma with or witho
neurologic signs, especially if
occurring after initial improvemen
Cardiac arrest
Adrenergic or neurologic signs;
rebound ketosis
Cardiac arrhythmias
Fever
SOURCE: Adapted from DW Foster, in Current Therapy in Endocrinology and Metabolism 1985
1986, DT Krieger, CW Bardin (eds), Toronto/Philadelphia, Decker, 1985.
Clues To Complications In DKA (2)
8/12/2019 Hyperglycemic Crises in Pa
49/55
H
Insulin resistance
Myocardial infarction
Mucormycosis
Respiratory distress syndrome
Vascular thrombosis
Unremitting acidosis after 46 h of
adequate therapy
Chest pain, appearance of heartfailure; appearance of hypotension
despite adequate fluids
Facial pain, bloody nasal discharge,
blackened nasal turbinates, blurred
vision, proptosis
Hypoxemia in the absence of
pneumonia, chronic pulmonary
disease, or heart failure
Strokelike picture or signs of
ischemia in nonnervous tissue
PREVENTION(1)
8/12/2019 Hyperglycemic Crises in Pa
50/55
H
Many DKA and HHS can be prevented by better
access to medical care, proper education, and
effective communication with a health care provider
during an intercurrent illness.
The observation that stopping insulinfor economic
reasons is a common precipitant of DKA in urbanAfrican-Americans is disturbing and underscores the
need for our health care delivery systems to address
this problem, which is costly and clinically serious.
PREVENTION(2)
8/12/2019 Hyperglycemic Crises in Pa
51/55
H
Sick-day managementshould be reviewed periodically
with all pts, include specific information on(1)when to contact the health care provider.
(2)blood glucose goals and use of supplemental short-
acting insulin during illness.(3)means to suppress fever and treat infection.
(4)initiation of an easily digestible liquid diet containing
carbohydrates and salt.
PREVENTION(3)
8/12/2019 Hyperglycemic Crises in Pa
52/55
H
Most importantly, pt should be advised never to
discontinue insulin and to seek professional adviceearly in the course of illness. Successful sick-daymanagement depends on involvement by pt and/orfamily member.
The p
t/family member must be able to accuratelymeasure and record blood glucose, urine ketonedetermination when blood glucose is >300 mg/dl,insulin administered, BT, RR , PR, and BW and must
be able to communicate this to a health careprofessional.
PREVENTION(4)
8/12/2019 Hyperglycemic Crises in Pa
53/55
H
Adequate supervision and helpfrom staff or family may
prevent many admissions for HHS due to dehydration
among elderly individuals who are unable to recognize or
treat this evolving condition.
Better educationof care givers as well as pts regarding
signs and symptoms of new-onset diabetes; conditions,procedures, and medications that worsen diabetes control
and use of glucose monitoring could potentially decrease
incidence and severity of HHS.
PREVENTION(5)
8/12/2019 Hyperglycemic Crises in Pa
54/55
H
Annual incidence rate for DKA from population-based studies
ranges from 4.6 to 8 episodesper 1,000 pts with diabetes, with
trend toward an increased hospitalization rate in the past twodecades. Incidence of HHS accounts for
8/12/2019 Hyperglycemic Crises in Pa
55/55
H
Because repeated admissions for DKAare estimated todrain approximately one out of every two health caredollars spent on adult type 1 diabetes, resources need to bredirected toward prevention by funding better access tocare and educational programs tailored to individual needincluding ethnic and personal health care beliefs.
In addition, resources should be directed toward educatioof primary care providers and school personnel to identifysigns and symptomsof uncontrolled diabetes and newlyonset diabetes can be diagnosed early. This has been showto decrease incidence of DKA at the onset of diabetes.