Download - Pancreas n DM
-
8/9/2019 Pancreas n DM
1/10
Pancreatic Diabetes Mellitus
Robert |. Sjoberg, MD
Gerald S. Kidd, MD
Diabetes mellitus caused by pancreatic exocrine disease
is a unique clinical and metabolic form of diabetes. The
diagnosis of pancreatic diabetes caused by chronic
pancreatitis may be elusive because it is occasionally
painless and often not accompanied by clinical
malabsorption until after hyperglycemia occurs. Diabetic
patients with pancreatic calcification or clinically
demonstrable pancreatic exocrine dysfunction will
manifest the unique aspects of pancreatic diabetes
described herein. Like other forms of diabetes, the
primary hormonal abnormality in pancreatic diabetes is
decreased insulin secretion. Patients with this disorder
are unique in that they have low glucagon levels that
respond abnormally to several physiological stimuli,
blunted epinephrine responses to insulin-induced
hypoglycemia, and malabsorption. In addition, they
often have concomitant alcohol abuse with hepatic
disease and poor nutrition. These characteristics result
in increased levels of circulating gluconeogenic amino
acids, decreased insulin requirements, a resistance to
ketosis, low cholesterol levels, an increased risk of
hypoglycemia w hile on insulin therapy, and the clinical
impression of brittle diabetes. Retinopathy occurs at a
rate equal to that of insulin-dependent diabetes but
may be less severe in degree. Other complications of
pancreatic diabetes have been less well studied but may
be expected to be seen more frequently as these
patients survive longer. The characteristics of pancreatic
diabetes suggest that a conservative approach be taken
in regard to intensive insulin therapy and tight blood
glucose con trol.Diabetes Care12:715-2 4, 1989
From the Endocrine Service, Department of Medicine, Fitzsimons Army Medical
Center, Aurora, Colorado.
Address correspondence and reprint requests to Gerald S.
Kidd,
MD, Endo-
crine Service, Department of Medicine, Fitzsimons Army Medical Center, Au-
rora,
CO
80045-5001.
The opinions and assertions contained herein are the private views of the
authors and are not to be construed as official or reflecting the views of the
Department of the Army or the Department of Defense.
A
lthough the exocrine and endocrine cells of the
pancreas are generally thought to function in-
dependently of each other, they are anatomi-
cally closely related. This anatomic relationship
allows pancreatic islet cell dysfunction to be associated
with and/o r caused by pancreatic exocrine disease. The
pancreatic exocrine syndromes known to be associated
with so-called pancreatic diabetes include acute and
chronic pancreatitis, postpancreatectomy syndrome,
cystic fibrosis, tropical pancreatic diabetes, and pan-
creatic carcinoma. This association is historically im-
portant because the role of the pancreas in causing di-
abetes mellitus was initially postulated 200 yr ago in a
report of a patient with diabetes who had pancreatic
calcifica tion (1). Pancreatic diabetes continues to be im-
portant because it is unique clinically, hormonally, and
metabolically, prompting the National Diabetes Data
Group to classify it as a distinct form of diabetes (2).
This review summarizes the clinical manifestations of
pancreatic diabetes, with particular emphasis on pan-
creatitis and postpancreatectomy syndrome. Diabetes
associated with cystic fibrosis and tropical pancreatic
diabetes is discussed briefly in comparison with other
forms of pancreatic diabetes, but it has recently been
reviewed in greater detail (3-5).
FREQUENCY
AND
DIAG NO SIS
Mild hyperglycemia may occur transiently in association
with acute pancreatitis up to 50% of the time and has
been used as a marker for the severity of pancreatitis
(6,7). Long-term follow-up of patients after a single ep-
isode of acute pancreatitis indicated that they had an
increased frequency of abnormal glucose tolerance
compared with an age-matched population (8). Such
DIABETES CARE, VOL. 12, NO . 10, NOVEMBER/DECEMBER 1989 715
-
8/9/2019 Pancreas n DM
2/10
PANCREATIC DIABETES MELLITUS
patients may have chronic painless pancreatic inflam-
mation in addition to their acute painful episode (6). A
distant history of acute pancreatitis may, however, be
etiologically important in any patient with diabetes.
The prevalence of abnormal glucose tolerance in pa-
tients with chronic pancreatitis was 60-70% and of overt
diabetes was 3 0- 40 % (6,9,10). Serial testing of individ -
ual patients with chronic pancreatitis demonstrated a
progressive deterioration of glucose tolerance over
time (6).
The presence of pancreatic calcifica tion increased the
occurrence of endocrine dysfunction, resulting in a 70%
prevalence of diabetes (6). Thirty-three percent of pa-
tients with chronic pancreatitis and diabetes had pan-
creatic calcification (6). Pancreatic calcification was
present in 20% of patients with chronic pancreatitis
but was more common in alcohol-induced (30%) and
tropical (75%) pancreatitis (4-6).
Chronic pancreatitis is painless 5-10% of the time,
and steatorrhea is a late manifestation of chronic pan-
creatitis, often occurring after the onset of diabetes
(6,9-11). This implies that the diagnosis of diabetes as
a result of chronic painless pancreatitis can be elusive.
Approximately 30% of patients with diabetes and cal-
cific pancreatitis in one large series were diagnosed by
abdominal roentgenography of patients previously thought
to have genetic diabetes (6). The data reported below
regarding the clinical and hormonal status of patients
with chronic pancreatitis were derived from patients with
either pancreatic calcification on plain roentgenography
or well-documented recurrent episodes of pancreatitis
associated with pancreatic exocrine insufficiency and
usually a known etiology for chronic pancreatitis. With
these points in mind, proposals regarding who in the
diabetic popu lation should be screened for and practical
clinical criteria for the diagnosis of pancreatic diabetes
are given in Table 1. Although these criteria may not be
inclusive, we feel that patients meeting these criteria w ill
manifest the unique aspects of pancreatic diabetes out-
lined below.
Little is known regarding the cause of chronic pan-
creatitis and any effect this may have on the diabetic
syndrome. Most patients studied have had alcohol abuse
as the cause for their pancreatic disease. This may sim-
ply reflect the most common etiology of chronic pan-
TABLE 1
Clues and criteria for diagnosis of pancreatic diabetes
Clues
Suspect pancreatic diabetes in any diabetic patient with:
One or more d ocumented episodes of acute pancreatitis
A known historical cause for chronic pancreatitis
Previous pancreatic surgery
Criteria
Patients have pancreatic diabetes if:
Pancreatic calcification is present on plain roentgenography
Steatorrhea partially reversible with pancreatic enzyme therapy
is demonstrable
creatitis, but it has also been suggested that alcohol-
induced pancreatitis results in a higher prevalence of
diabetes than other etiologies of pancreatitis (6,9,11).
Cystic fibrosis results in diabetes less frequently than
chronic pancreatitis, its prevalence being 7-15% of cys-
tic fibrosis patients >18 yr of age (3). Tropical pan-
creatic diabetes differs from other causes of pancreatic
diabetes in its higher insulin requirements (4,5). Total
pancreatectomy generally results in a more severe de-
gree of endocrine dysfunction than chronic pancreatitis,
but resection of
-
8/9/2019 Pancreas n DM
3/10
R.J. SJOBERG AN D G.S.KIDD
1050
9 0 0
^ 750
40,000, but low levels of 3500-M
r
glucagon were
occasionally detectable in such patients (31-33). The
paradoxical increase in immunoreactive glucagon after
oral glucose ingestion was also caused by an increase
+80
+
60
+
40
+20
- 2 0
1 4 0 r B
120
\
-1
1 0 0
I
8 0
6 0
3
2 0
0
L
5- -S--
-
8/9/2019 Pancreas n DM
4/10
PANCREATIC DIABETES MELLITUS
in a 9000- to 15 ,000-M
r
fraction of immunoreactive glu-
cagon (34).
The source of the low levels of 3500-M
r
glucagon in
pancreatectomized humans is unclear. All pancreatec-
tomized patients studied have also had a partial duo-
denectomy and often an antrectomy, ruling out these
tissues as potential glucagon sources. The possibility of
peripheral conversion of gut-derived high-molecular-
weight glucagon to 35OO-M
r
glucagon must also be con -
sidered (35).
AMINO ACID METABOLISM
Plasma amino acids, especially those that serve as
substrates for gluconeogenesis, were elevated postpan-
createctomy compared with normal or IDDM levels
(31,32,36-39). Maintenance of normoglycemia for 24 h
with a glucose-controlled insulin infusion system did not
decrease these gluconeogenic precursors to normal as
it did in IDDM (38). A physiological glucagon infusion
did, however, normalize amino acid levels, suggesting
that hypoglucagonemia mediates hyperaminoacidemia
(32,37,39).
FATTY ACID AND KETONE BODY METABOLISM
Studies concerning fatty acid metabolism postpancrea-
tectomy helped clarify the role of glucagon in the de-
velopment of ketoacidosis. Withdrawal of insulin from
fasting pancreatectomized patients resulted in ketoaci-
dosis, but blood ketones and glucose rise less markedly
over time than in IDDM patients (40,41; Fig. 3). No
difference was found between these two types of dia-
betes in free fatty acid increments (40). IDDM patients,
unlike pancreatectomized patients, had a marked in-
crease in glucagon concentration during development
of ketoacidosis (40; Fig. 4). These data suggest that
hyperglucagonemia promotes hepatic conversion of free
fatty acids to ketone bodies, but in view of the detect-
able plasma levels of 3500-M
r
glucagon found in some
pancreatectomized patients, the absolute need for glu-
cagon in the development of ketoacidosis remains un-
15-i STOP
INSULIN
2 10
o
o
o
5 -
0
J
0 -
i i
-1 0
4 8
TIME (hours)
12
- 1 0
4 8
TIME (hours)
12
FIG. 3. Changes in blood concentrations of 3-hydroxybutyrate and glucose in 6 patients with insulin-depende nt dia-
betes () and 4 pancreatectomized patients (O) after withdrawal of insulin. Values are means SE.*P
-
8/9/2019 Pancreas n DM
5/10
R.J. SJOBERG AND G.S. KIDD
30
1
o
o