Acute and Chronic Complications of Diabetes Mellitus in

Older Patients

DOUGLAS A. GREENE, M.D. The chronic complications of diabetes are thought to be caused by
Pittsburgh, Pennsylvania an interaction between hyperglycemia or other metabolic conse-
quences of insulin deficiency and other poorly defined independent
genetic or environmental factors. Several important biochemical
sequelae to hyperglycemia are discussed. Macrovascular disease
appears to be primarily age-related in diabetic patients. The clinical
course, manifestations, and management of diabetic complications
are significantly altered when they appear against a background of
the degenerative changes of aging, greatly complicating diagnosis
and management. In elderly patients, the acute complications of
diabetes-ketoacidosis and hyperosmolar dehydration-often
occur in the context of chronic complications that greatly com-
pound their management and increase their morbidity and mortality.
METABOLiCANDFUNCTlONALCONSEQUENCESOF
HYPERGLYCEMIA
The pathogenesis of diabetic complications is currently viewed as a com-
plex interaction involving hyperglycemia and/or other consequences of
insulin deficiency, along with other poorly defined independent genetic or
environmental factors. These factors interact to produce a sequence of
events in susceptible tissues that culminates in clinical complications
such as angiopathy, nephropathy, neuropathy, and retinopathy. Thus,
abnormalities in tissue biochemistry resulting from hyperglycemia are
thought to lead to alterations in target-tissue function, then to the devel-
opment of structural lesions in target tissues, and finally to the overt clini-
cal complications (Figure 1).
Several of the metabolic abnormalities that are directly related to hy-
perglycemia have now been defined in target tissues such as blood ves-
sel, retina, renal glomerulus, and peripheral nerve [l]. In these tissues,
glucose entry is neither rate-limiting for its metabolism nor modulated by
insulin. Elevation of blood glucose levels, therefore, results in elevated
glucose concentrations in tissues, leading to excess glucose metabolism
through the polyol, or sorbitol, pathway. This pathway consists of the
conversion of glucose to sorbitol by the enzyme aldose reductase and
then to fructose by the enzyme sorbitol dehydrogenase (Figure 2). The
activity of this pathway is highly dependent upon the glucose content in
tissues. This metabolic pathway is active in almost all tissues that are
From the Department of Medicine, School of Medi- susceptible to the complications of diabetes, including nerve [l], retina
tine, University of Pittsburgh, Pittsburgh, Pennsyl- [2], renal glomerulus [3], and blood vessel [4].
vania. Requests for reprints should be addressed A second biochemical abnormality in target-tissue metabolism related
to Dr. Douglas A. Greene, Clinical Research Cen-
ter, 3304 Presbyterian University Hospital, Piis- to hyperglycemia involves myo-inositol, a six-carbon cyclic polyol that is
burgh, Pennsylvania 15261. ubiquitous in both plant and animal cells, and which bears an interesting

May 16, 1986 The American Journal of Mediclne Volume 80 (suppl 5A) 39
SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

Environmental Variables

ABNOljMALlTlES IN IN TARGET IN TARGET COMPLlCATlONS

TARGET TlSSUES TISSUE FUNCTION TISSUES

t Polyol pathway J Nerve conduction AxonopathyldemyelinPion Neuropathy

J myo-inositol J AfQS function Mesangial proliferation Nephropathy
Glyizosylation J Sensory function Retinal vascular changes Retinopathy
1‘ GFR
Blood-vitreal leak

GFR = glomerular filtration rate

Flgure 1. Glucose hypothesis of ‘diabetic complications. Biochemicallfunctional &uctural scheme.

NADPH NADP+ NAD+ NADH

GLUCOSE u SORBITOLu FRUCTOSE

aldose sorhitol
redudtase dehydrogenase
F/g& 2. The sorbitol pathway. The enzymes aldo$e reductase and sorbitol dehydrogenase are found in many tissues, but in
hea@y individuals significant production of fructose is seen only in tee prostate. Since the rltacfon is dependent on the
condtihtrati~ of Substrate, diebetes leads to an increase in polyol pathway activity by virtue of increased glucose concentration
in tissue+ This effect has beeti demonstrated in the lens, peripheral nerve, renal glomerulus, and retina. Reproduced with
permission of the Amedcan Diabetes Association from [I].

my?-inositol D-glucose
L
Figure 3; Myo-k?ositoland glucose structures. M@4?ositoi is a cyciic hexahydroxy hexanol found in high concentrations in
most mammalian t&sues, including nerve. It is rapidly and reversibli incorporated into a labile cl&s of phospholipids, the
phoSphoinosi#des, which are thought to have important membrane functions. It is synthesized from glucose-Sphtiphate. Its
three-dimeMona/ structure is similar to that of glucose, which ibhibits the uptake of myo-inositof in nerve. Reproduced with
permission of the American Diabetes Association from [l].

structural similarity to glucose (Figure 3). In many in-
stances, giucose functions as a competitive inhibitor of
carrier-mediated uptake of myo-inositol into a variety of
tissqds, poteniial!y leading to depletion of myo-ino$itol in
hypqglycemia [5]. Myo-inositol levels are reduced by
hyperglycemia in most tissues that are susceptible to dia-
betic complicatioris (l-41. Myo-ino$tol, a hormal dietary
cdnstituent for most mamm$ls-including hu,mans-is
absotied across the intestinal lumen by carrier-mediated
sodium-cotransporl [S], circulates in plasma, and is fil-
tered and then reab$orbed by the kidney [?I (Figure 4).
Glucose competes for !he,niyo-inositol trqnsporter in rerial
tubular membranes, leading to increased urinary excre-
t/o? of myq-inbsitol in diabetit p&tier&. Most &lls main-
tain myo-inositol concentrations that are @eraI orders of
magnitude greater than plasma cdncentrations, either
through endogenous synthesis from E)lucose-bphosphate
or sodium-dependent uptake from plasma, or both. The

46 May l&l956 The American Journal of Wlclne Volume 50 (suppl5A)

 INTESTINE
DIET

Figure 4. Myo-inositol metabolism. Myo-

inositoi, a normal dietary constituent for
most mammals, is absorbed from the in-
testine by carder-mediated sodium- KIDNEY
dependent transport, circulates in
plasma at mlctomoiar concentrations,
and is filtered, reabsorbed, and oxidized
w7 J CELL
by the kidney. Most ceils contain concen-
trations of myo-inositoi greatly exceeding -* Glucose-6-P
that in plasma by vi&e of either endoge-
nous synthesis andlor “active” (sodium-
dependent) transport. The major meta-
bolic pathway within cells (other than in
the kidney) is reversible incorporation
into inositol-containing phosphoiipids,
the phosphoinosit/des. Glucose competi-
tively inhibits sodium-dependent myo-
inositol transport in the intestine, kidney, --4A FA/
and nerve.

Ptdlns Ptdlns4P PtcJlns4,5P, Discylglyosrol

/ / /

Figure 5. Phosphorylation-dephospho-
ryfatfon pathways of phosphoinosiffde
metabolism. These phosphoin&tides
are mainly confined to the inner leaflet of
SL
the plasma membrane. Agonists act by
sbimuiating the hydrolysis of Inositol4,5-
diphosphate (Ptdlns4,5Pd by a phos-
phodiesterase enzyme to give diacyf-
g&cero/ and in&to/-1,4,5-b&phosphate
(Ins 1,4,5P3). Reproduced with permis-
sion horn Berridge AM: Inositol triis-
phosphate and diacylglycerol as second
messengers. Bochem J 1984; 220: 345- lns1,4,5P,
360.

major metabolic fate of myo-inositol within cells is reversi-
ble incorporation into a unique class of phospholipids-
the phosphoinositides-oonsisting of phosphatkfylinosi-
tol, phoaphatidylinoaitol-4-phosphate, and phosphatidylin-
ositol-4,5biaphoaphate. Agonist-mediated hydrolysis of
phosphatidylinositol-4,5bisphosphate has been linked to
the intracellular release of two catabolltes that function as
intracellular vrs with important regulatory func-
tion, diaoylglycerol, and inositol-1,4,5Msphosphate (Flg-
we 5).
The polyol pathway and myo-inositol metabolism have
been linked together in a metabollc relationship involving
the sodium pump ([Na+,K+]-ATPase) in tissues that are
susceptible to diabetic complications (Figure 5). Hyper-
glycemia leads to abnormalities in myo-inositol uptake in a
variety of tissues susceptible to diabetic complications
[4,71. In addition, metabolism of glucose by the polyol
pathway also contributes to depletion of myo-inositol in
tissues by mechanisms that are poorly understood, since
aldose reductase inhibitors completely prevent the decline
in tissue myo-inositol in diabetic nerve [l], kidney [3], and
blood vessel [4]. Depletion of myo-inositol leads to sec-
ondary alterations in membrane phosphoinositide metab-
olism that, in turn, result in alterations in a variety of mem-
brane-bound enzymes, including (Na+,K+)-ATPase. The
link between membrane phosphoinositide metabolism

M8y 16, l@M The An&can Journal of Medklna Volume 80 (suppl SA) 41
SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

Hypergria -)

Competbe
Inhibition tmw&pY

I
J, Nai,-;;rktdent

J, Na+-Dependent \
I
Amino Acid - & Na+/K+ ATpaee J
uptake r Activity TMY

Altered
Phosp~speide /
Na+-Dependent
Processes

1
7 Other Effects

Figure 6. Metabolic web. Postulated relationship between hyperglycemia, polyol pathway, myo-inositol (Ml), (Na+,K+)-
ATPase, and nerve conduction in diabetes. Glucose at hyperglycemic concentrations reduces nerve myo-inositol by competi-
tively inhibiting its uptake. Increased polyol pathway activity, also a consequence of hyperglycemia, f&her contributes to
reduced nerve myo-inositol by an as yet undefined mechanism(s). The reduction in nerve myo-inositol leads to a decrease in
(Na+, K+)-ATPase activity, possibly through an alteration in phosphoinositide metabolism. Since myo-inositol uptake in nerve is
sodium-dependent, a self-reinforcing metabolic cycle involving myo-inositol is postulated. The acute reduction in nerve conduc-
tion velocity in diabetes is ascribed in part to impaired (Na+, K+)-ATPase activity. A further consequence of such impaired
activity is a reduction in sodium-dependent amino-acid uptake; interference with other sodium-linked processes is likely but as
yet unproved. Defects resulting from reduced nerve myo-inositol levels other than those mediated by changes in (Na+,K+)-
ATPase await further investigation. Reproduced with penission of the American Diabetes Association from [I].

and (Na+,K+)-ATPase appears to be related to protein covalently linked in a concentration-dependent manner to

kinase C [8]. These defects may play an important
pathogenetic role in the complications of diabetes. In at
least one tissue-peripheral nerve-the reduction in
(Na+,K+)-ATPase is related to an abnormality in tissue
function that occurs in experimental diabetes, the slowing
of nerve conduction velocity. The axolemmal (Na+,K+)-
ATPase generates the electrochemical sodium gradient at
the node of Ranvier necessary for saltatory impulse con-
duction by extruding sodium ions from the axoplasm.
Reduced (Na+,K+)-ATPase activity results in a fourfold
increase in intra-axonal sodium ions in large myelinated
nerve fibers in the diabetic rat, resulting in subthreshold
membrane potentials and either nodal delay or frank con-
duction block of these rapidly conducting fibers, producing
slowed composite nerve conduction velocity [9]. Hence, in
one tissue, we can now, through a series of steps, logi-
cally relate hyperglycemia to a defect in tissue function
that is characteristic of the diabetic state: the slowing of
nerve conduction.
The other glucose-derived abnormality in metabolism
that probably plays a significant role in the development of
complications is nonenzymatic glycosylation of protein
[lo]. This process also occurs at an accelerated rate in
diabetes in only those tissues where glucose entry is not
rate-limiting for its metabolism and where insulin does not
modulate overall glucose utilization. Glucose becomes
the end-terminal amino acid of a variety of proteins, lead-
ing to nonenzymatic glycosylation. The model for such
nonenzymatic glycosylation in diabetes is the formation of
glycohemoglobin [lo]. Glycosylated residues can become
irreversibly cross-linked, leading to macromolecular pro-
tein aggregates that substantially alter the characteristics
of both the intracellular milieu and the extracellular matrix.
These so-called advanced glycosylation products have
been implicated in changes in vessel permeability, trap-
ping of plasma proteins such as immunoglobulins and lip
oproteins in the extracellular matrix, enhanced immuno-
genicity of native peptides, and the release of cytotoxic
oxidative metabolites [lo]. In summary, there are a variety
of adverse effects of hyperglycemia on target-tissue me-
tabolism that can be invoked to explain the relationship
between hyperglycemia and long-term chronic alterations
in target-tissue function and structure.
THE ROLE OF HYPERGLYCEMIA IN THE CHRONIC
COMPLlCATlONS OF DIABETES
The ideal evidence establishing a role for hyperglycemia
in the pathogenesis of diabetic complications would be a
well-conducted prospective intervention study in which
various glucose levels maintained over time are related to
the development and/or progression of clinical complica-
tions of diabetes. Although such long-term studies are

42 May IS,1986 lb American Journal of Medicine Volume 80 (suppl 5A)


Change in
Change in
Creatinine
Clearance
Figure 7. Prospective intervention re- mlfmin
sults in type I diabetic patients, compar-
ing “usual” therapy versus intensified Change in
insulin arld dietary therapy. Changes are ,ndex
Retinopathy
from the time of entry (year zero) to year
one and year two (with the exception of
hemoglobin A,c (HgbAfcJ for which val-
ues are given at the time of entry and the Change in
mean of all values [excluding entry] over
on6 year and over two years). Repro-
duced with permission from [l l].
now under way (e.g., the Diabetes Control and Complica-
tions Trial sponsored by the National Institutes of Health),
no such data are as yet available. Several pilot studies for
such long-term, randomized, controlled, prospective inter-
vention trials have been completed, however, with slightly
conflicting but generally encouraging results.
PROSPECTIVE INTERVENTION STUDIES IN TYPE I
DIABETIC PATIENTS
Holman et al [l l] studied 74 type I diabetic patients ran-
domly assigned to “usual” or intensified ,insulin and die-
tary therapy for 24 months. The level of hemoglobin A,c
was significantly reduced by intensive insulin therapy. Uri-
nary albumin excretion (microalbuminuria) and the vibra-
tory perception threshold were assessed as measures of
subclinical nephropathy and neuropathy. Urinary albumin
excretion and vibratory threshold increased in the con-
ventionally treated group (though not to levels that would
ordinarily be detected in clinical practice) and decreased
in the intensively treated group (Figure 7). This suggests
that intensive insulin therapy prevents deterioration of
subclinical renal and peripheral nerve defects that would
otherwise occur in patients with type I diabetes. Since nei-
ther of these functional defects constituted clinically overt
complications, however, the efficacy of intensive insulin
May 16,198s
SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE
Year 0 Year 1 Year 2
25
-j/-+---{N.S.
therapy in preventing clinically significant complications
remains unanswered.
A study by Service et al [12] supports Holman’s results.
This study randomly assigned type I diabetic patients to
either conventional or continuous subcutaneous insulin
infusion (“pump”) therapy. Within eight months, statisti-
cally significant differences were found in nerve conduc-
tion and vibratory threshold that favored the group that
received continuous subcutaneous insulin infusion:
In a third study [13], 70 type I diabetic patients were
assigned to either conventional or continuous subcutane-
ous insulin infusion therapy, and the progression of micro-
albuminuria and retinopathy (graded on stereofundus
photographs) were followed. Within eight months of
follow-up, this multicenter study confirmed the beneficial
effect of intensive insulin therapy on microalbuminuria
(Figure 8), but demonstrated a significaht acceleration of
retinopathy, particularly the appearance of soft exudates,
in the group that received continuous subcutaneous insu-
lin infusion therapy (Figure 9). This latter finding-
increased numbers of soft exudates-confirms the earlier
observations of the Steno Group [14] demonstrating ac-
celerated retinopathy with intensive insulin therapy. Thus,
if increasing microalbuminuria and vibratory perception
threshold and/or slowed nerve conduction are true harbin-
The American Journal of Wlclm Volume 80 (suppl SA) 43
SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

N=lO

Figure 8. Prospective intervention re-

sults in type I diabetic patients with su-
pranormal baseline albumin excretion
values (exceeding 12 rq per minute).
Conventional injection treatment (left)
versus continuous subcutaneous insulin
I I I I I I infusion (right). Adapted by permission
0 4 0 0 4 6 of The New England Journal of Medicine
Months Months
1982; 307: 3690.

RklNOPATHY LEVEL RETINOPATHY LEVEL

MEAN KEYED TO WORSE EYE

. *,,g(’ 65 /65-
65<65-
I 50 /50-
g 40 . . ,w 50<50-
s l ,/‘8 2 4q I40- .
230 x- s40<40- l ,i -

A4 g30/30- ,’
2d 30<30- 8’
/ Fibwe 9. Prospective intervention re-
20 I zo-
10 20 c zo- sults in type I diabetic patients, compar-
d cl-r CIT
/ 10 I lo- jg’ ing conventional injection treatment (C/T)
/
0
i versus continuous subcutaneou$ insulin
10 20 30 40 50 60 70
Baseline infusion (CSII). Retinopathy levels shown
are at baseline and eight inonths. Values
701 falling on the broken identity line indicate
. no change, those falling to the left of the
@I- /@ line indicate deterioration, and those fall-
65 I65- . ing to the right indicate improvement. Val-
50- ,,,&” 65 c 65-
ues obtained by both methods used to
50 t 50-
c 40- 8 i rjr’ assess the retinopathy level (mean level
g 50
40 cI 40-
50- - “A ,g’
5i5 . 8 / and the system keyed te the worse eye)
m 30- -,/. 5 40 c 40- are shown for comparison. The unjts of
/ $30130- seventy are arbitrary; intervals with the
zo- 30 < 30- same numeric value may represent dif-
/
20 t 201 /
lo- ,,,$$dg40*”
ferent degrees of clihical change.
CSII Shaded areas indicate the retinopathy
/ I I I I I levels in those patients initially selected
0 10 20 30 40 50 60 70
Baseline
for the trial, but not meeting the eligibility
criteria with respect to retfnopathy.
Adapted by permission of The New Eng-
land Journal of Medicine 1982; 307: 652.

44 May 16,1986 The American Journal of Medicho Volumb 80 (suppl5A)

 SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

r
loo-
200-
; 300-
$ 400-
5 500-
:' 600-
700 -
aoo-

loo-
200-
300-
400-
500-
600-
700 -
aoo-
8f 900-
lOOO-
FI llOO-
z” 1200-
1300-
1400
r
1500
1600
1700
1800 40
Figure IO. Increasing annual incidence 1900 1 30
Oh
(top) and prevalence (bottom) of ne-
phropathy as a function of the known du-
ration of diabetes. Reproduced with per-
mission of the American Diabetes Asso- Known Duration (years)
ciation from [16].

gers of clinically overt complications, then long-term inten-
sive insulin therapy should delay or prevent the develop
ment of these complications. On the other hand, the ac-
celerated development of soft exudates with the institution
of intensive insulin therapy is worrisome, although the
clinical implications of this @tding are unclear. Long-term
clinical intervention trials that assess both clinical and
subclinical retinopathy, nephropathy, and neuropathy-
such as the Diabetes Control and Complications Trial-
are sorely needed to clarify the role of blood glucose con-
trol in the development and progression of diabetic com-
plications [151.
LONG-TERM STUDIES OF TYPE II DIABETIC PATIENTS
Blood glucose intervention studies are usually performed
in type I diabetic patients because of the ease in patient
classification and the clear-cut dating of the onset of dia-
betf3B. Studies including patients with type II diabetes are
more directly relevant to the problems in the elderly. The
only available long-term study involving type II diabetic
patients (according to the current diagnostic and classifi-
cation criteria) that relates complications to the degree of
diabelic control is Pirart’s unique 25year prospective
study of 4,400 unse@ted patients in a diabetic clinic [16].
In this natural history study, blood glucose control re-
flected the severity of the diabetes and the extent of pa-
tient compliance with a general treatment regimen rather
than a specific form of intervention. Glucose “oontrol” was
assessed annually according to semi-objective and semi-
quantitative criteria [ 161. Complications were assessed
clinically, e.g., neuropathy on the basis of clinical exami-
nation and history, retinopathy by clinical funduscopy, and
nephropathy by the presence of azotemia and/or macro-
proteinuria. The prevalence and incidence of nephropa-
thy, neuropathy, and retinopathy increased progressively

May l&1986 The American Journal of Med!cine Volume 80 (suppl SA) 45

 SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

I
3
0B 03 I,,,,,, yLc”“““‘-“” 2924 27 332015 16 14
d 200 r60

40
%
20

60

- 100

- 60 Figun, 11. lncreasi& prevalence of

neuropathy as a fimciion of the known
- 60 duration of diabetes in four age groups at
- %
the onset. If the two below-age40 cate-
- 40
gories are grouped Jpgether and com-
20
pared with the two over-age40 groups,
% the dit7erences in prWa/ence relate to the
03 first nine years, the “yoqg” group being
0 1 2 3 4 5 6 7 6 9 1011 12 13 141516 17 1619202122232425 affected later than the “M’ group.
Known Duration (years) Adapted with permission of the American
Diabetes Association from [IS].

with the duration of diabetes (Figure lg), but did not differ
substantially as a function of age at the time of the diagno-
sis of diabetes (Figure 11). This suggests that these “car-
dinal” complications occur in a similar manner in patients
with type I and type II diabetes despite fundamental differ-
ences in the pathogenesis of the underlying metabolic
abnormality [i6]. This conclusion must be tempered by
the fact that Pirart had relatively few adolescents in his
cohort, that complications were slightly more common in
older patients within the first five years after the diagnosis
of diabetes (Figures 11 and 12) and that other studies,
with a greater proportion of young patients, suggest a
possible protective effect of prepuberty on the develop-
ment of diabetic retinopathy. In Pirart’s study, retinopathy,
neuropathy, and nephropathy were all more common in
diabetic patients in whom the disease was poorly con-
trolled (Figure 13). Thus, these three complications ap-
pear to be primarily related to the duration and seventy of
hyperglycemia, rather than to the cause of hyperglycemia,
with age as an additional modulating factor. In contrast,
macroangiopathy in diabetic patients is primarily related to
attained age rather than to duration and severity of diabe-

46 May 16,1986 The American Journal of MedIcha Volume 80 (suppl 5A)

 SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

3
58 3”““““““““““““’ 2924273328 1518 14
200
P

20 Age 5 20 20
% %’
03 E0

ii
d
6 200
z”

20 20CAgeI40 20
% %
0 3 0

20 20
46 3 E %
0 0

200

I 400
0
F 600
P
800 40

Figure 12. increasing prevalence of 20 20 o/o

nephmpathy as a function of known du- %
ration of diabetes in four age groups at 03 0
onset. Reproduced with permission of 0 1 2 3 4 5 6 7 8 910111213141516171819202122232425
the American Diabetes Association from Known Duration (years)
IW.

tes. As discussed by Drs. Wilson and Kannel elsewhere in
this issue, diabetes is only one among several other pri-
mary risk factors associated with increased cardiovascu-
lar mortality. In summary, the frequency of the cardinal
complications of diabetes-retinopathy, neuropathy, and
nephropathy-increase with both the duration and sever-
ity of hyperglycemia, with a small but significant contribu-
tion from aging. Macroangiopathy, on the other hand, is
selectively more frequent in elderly diabetic patients in an
age-dependent fashion. Thus, the impact of hyperglyce-
mia is magnified when superimposed on the background
of aging.
MECHANISMS BY WHICH AGING COULD INFLUENCE
DIABETIC COMPLICATIONS
There are a variety of factors in the natural aging process
that could influence the pathogenesis, expression, and
impact of diabetic complications at biochemical, physio-
logic, and clinical levels. Recent evidence in diabetic rats
suggests that sex steroids or other factors eliminated by
castration enhance sorbiiol accumulation and myo-inosi-
tol depletion in microvascular tissue [17J, providing a po-
tential mechanism by which puberty might condition the
development of microvascular complications. A second

May l&l955 The American Journal of Medicine Volume 50 (suppl 5A) 47

SYMPOSIUM ON DIABETES IN ME ELDERLY-GREENE
dO
I0 100
200
B 300
p 400 3
dO
m
200
100 I
8300
p 400
20
9b 'i 1
10
20-I
110111111111111%~
1 2 3 4 5 6 7 6 910111213141516171619202122232425
biochemical interaction between diabetes and aging oc-
curs via nonenzymatic protein glycosylation [lo]. As dis-
cussed earlier, intracellular or extracellular proteins ex-
posed to elevated ambient glucose concentrations un-
dergo nonenzymatic conjugation with glucose at the
N-terminal and other free nitrogen groups, leading to the
formation of glycosylated proteins. Long-lived glycosyl-
ated proteins are subsequently cross-linked at glycosyla-
tion sites, forming larger macromolecular structures called
“advanced glycosylation products” [lo]. This process sig-
nificantly alters the behavior of serum proteins and immu-
noglobulins, triggering autoimmune responses and giving
rise to potentially toxic metabolic endproducts [lo]. Since
nonenzymatic glycosylation occurs in the absence of hy-
perglycemia, but at a much slower rate [lo], proteins with
long half-lives become progressively glycosylated with
age in nondiabetic individuals, thus providing another po-
tentially additive or synergistic interaction between diabe-
tes and aging in the pathogenesis of diabetic complica-
tions.
Diabetic nephropathy exhibits another potentially im-
portant interaction between aging and diabetes. The natu-
ral history of diabetic renal disease is currently viewed as
a long-term complex process [18] (Figure 14). The first 15
years of diabetes constitutes a “silent period” with abnor-
46 May 16,lS86 lha Amarkmn Joumal ol Mdkinm
60
70
60
50
40% Figure 13. Ascending curves for the dif-
30
20
ferent grades of Mhopatiy as a function
10 of the duration of the disease in patients
t 0 with good cumulative gtycemk conbol
OW, mdiocre cmboi Wddh~, or poor
control (boiiom). Adapted with permis-
don of the Ametican Diabetes Associa-
tkm ham [16].
mally high renal function, as Bss88s8d by renal blood fbw
or creatinine clearance, and subclinical but abnormal urf-
nary protein loss (microproteinurfa) that can be detected
only by sensitive laboratory techniques. Renal hypertro-
phy and hyperplasia are commensurate with hyperfiltra-
tion, resulting in increased kidney size and weight [19].
These abnormalities are more prominent in patients with
newly diagnosed type I diabetes and are only partly cor-
rected with initiation of insulin replacement therapy. Cre-
atinine clearance and microproteinuria remain efevated
for most of the duration of the disease, after which renal
function declines precipitously with the appearance of
clinically detectable macroproteinuria [18]. Micropro
teinutia and renal hyperfunction reflect the Insulin defi-
ciency, since they respond to insulin replacement [20].
Persistent hyperfunctfon is thought to progressively
damage renal gkxneruli, leading to compensatory aug-
mentation of single-nephron glomerular ffltratk~ in surviv-
ing nephrons, causing further damage that resutts in
eventual decompensation with the appearance of clini-
cally overt diabetic renal disease. Thii view implies that
other factors that diminish the functioning renal mass,
such as aging, hypertension, intrarenal vascular insuffi-
ciency, and so on, would acceferate the process initiated
by diabetes [21] (Ftgure 15). Thii is best illustrated by the
Volum 80 (ruppl SA)
 SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

COURSE OF DIABETIC GLOMERULOSCLEROSIS

Silent Phase - (- Clinical Disease +

160

Figure 14. Natural history of d@betic

glomerulosclerosis. Composite drawing
showing course of diabetic nephropathy.
Exercise and other stress will cause inter-
mlttent proteinuiia before a sustained
protein leak teads to a nephrotic syn- 25
drome. Reproduced by permission of Years of Insulin Dependence
Grune & Stratton from [18].

Figure I$. Role of sustained incr6ments

in glometular pressures and flows in the
initiation and progression of glomerular
sclerosis. Reproduced by pqmission of
The New England Journal of Medicine
1982; 307: 657.

role of associated hypertekion in the progression of es-
tablished dkbetic renal disease.
Advanced diabetic neptiropattiy, characterized by per-
sistent macroproteinuria kind mild systemic hypertension,
is not reversible with ihstitution of intensive insulin treat-
ment [22]. However, treatment of the associated hyper-
tension, itself a cause of increased renal perfusion, dimin-
ishes the rate at which overt renal disease progresses to
renal failure in dkbetic patients [23] (Figure 16). There-
fore, one wou!d expect that diminished renal reserves and
increased bi* pressure in elderly diabetic patievts
would increase their liability from diabetic rehai disease.
independent variables, many influenced by the aging
process, seem to pjay an important role iri the expression
or course of the complications of diabet& dnce they be-
come manifest. These independent facto& can often
serve as the focus for treatment that proiongs useful ijfe
and clinical well-being in these elderly patients. This form
of interaction is demonstrated in a practicqi sense by dia-
betic foot problems, which involve diabetic neuropathy,
diabetic or senile peripheral vascular insufficicincy, atid
social neglect.

May l&l999 The American Journal of MerJkine Volume 50 (suopl 5Aj 49

SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE

mllmn
month BeforeTreatment:2~ = 0.018 ml/mn
month BeforeTreatment:2p = 0.065
2.0- 2.0 -

1.5- 1.5-
During Treatment:2p = 0.015
/
0

l.O-
l.O-

0.5- 0.5-

O- O- 0
I I I I I I I I I
140 150 160 170 180 mm Hg 90 100 110 120 mm Hg

Figure 76. Decline in glomerular filtration rate during antihypertensive treatment, and systolic blood pressure (ieft) and dia-
stolic blood pressure (right). Reproduced by permission of Grune & Strarton from 1231.

Neuropathic foot ulceration results from a decreased
pain sensation plus abnormal proprioception, which com-
bine to shift weight bearing to abnormal sites on the sole
of the foot. Elderly patients have a variety of independent
architectural problems related to weight bearing and sen-
sation in their lower extremities that compound the ex-
pression of diabetic neuropathic foot ulcers. Elderly pa-
tients are less likely to bring these to the physician’s atten-
tion. The podiatric abnormalities related specifically to dia-
betes are often hidden by other architectural degenerative
changes of aging and consequently may be overlooked. A
similar situation exists in diabetic autonomic neurobathy
of the bladder, easily diagnosed in the young diabetic pa-
tient because of overflow incontinence, but dismissed in
the elderly patient as senile incontinence. The chronic
complications of diabetes interact with the aging process
at every level in their development, from the biochemical
responses to hyperglycemia to the clinical expression of
far advanced complications.
ACUTE COMPLICATIONS OF DIABETES IN THE
ELDERLY
Although elderly diabetic patieqts are prone to all of the
acute complications of diabetes, including ketoacidosis,
one complication takes on particular importance with geri-
atric patients: hyperosmolar coma. Hyperosmolar coma
has been described by a variety of terms, ind~dmg ‘Ay-
perosmolar hyperglycemic nonketotic coma” and “hyper-
glycemic dehydration syndrome.” The multiplicity of
names reflects general disagreement over the relative
importance of pathophysiologic elements in its clinical
presentation [24]. Although ketosis and anion-gap acido-
sis are rare, there are no rigidly defined exclusion criteria
for this loosely described disorder, so that the nomencla-
ture has been simplified to the “hyperglycemic dehydra-
tion syndrome” [25], and the definition broadened to in-
clude all patients with severe hyperglycemia, dehydration,
and hyperosmolarity in the absence of severe ketosis. Al-
though hyperosmolar coma accounts for only 5 to 15 per-
cent of all admissions for “diabetic coma” [26], its contri-
bution to overall mortality is much greater because of its
nearly 50 percent mortality rate [27,26]. Hyperosmolar
coma characteristically appears in elderly patients with
multiple complicating medical problems, which frequently
include some component of renal insufficiency; therefore,
the reported high mortality must be viewed in the context
of a high-risk population.
Hyperosmolar coma usually presents in patients over
the age of 60, one half of whomhaveeither undiagnosed
or untreated diabetes. Central nervous system derange-

50 May 16,1986 The American Journal of Mediche Volume 80 (suppl 5A)


ments frequently dominate the presentation, although
other systemic symptoms are often present. Antecedent
chronic illness is generally the rule, as are precipitating
drugs that decrease insulin secretion, interfere with insulin
action, or promote dehydration. In some studies, 80 per-
cent of the patients with hyperosmolar hyperglycemic
coma have moderate to severe renal insufficiency [28].
Additional precipitating factors include hypothermia, acute
pancreatitis, thyrotoxicosis, the use of diazoxide, propran-
0101,or cimetidine, hypertonic peritoneal dialysis, intrave-
nous hyperalimentation, and the ingestion of large
amounts of sugar-containing beverages [28]. General
debilitation, clouded consciousness, and chronic institu-
tionalization, which may interfere with the normal thirst
mechanism, are frequently involved.
Since hyperosmolar coma characteristically occurs ei-
ther in elderly patients with type II diabetes or in patients
with a history of only minimally impaired glucose toler-
ance, insulin deficiency is thought to be less severe than
in diabetic ketoacidosis, but measured insulin levels in
hyperosmolar coma are surprisingly low [29,30]. This is
thought to reflect longstanding hyperglycemia leading to
exhaustion of pancreatic beta-cell insulin reserves [31].
The lack of ketosis in these severely insulinopenic hyper-
osmolar patients remains unexplained [29,30].
The osmotic diuresis produced by hyperglycemia is
normally followed by a compensatory stimulation of the
thirst mechanism and polydipsia. However, in patients
with impaired or unexpressed thirst mechanisms, water
and salt losses are not counterbalanced by polydipsia,
leading to decreased extracellular fluid volume, renal hy-
poperfusion, and prerenal azotemia [26]. Thus, renal glu-
cose excretion, the “glucose safety valve,” becomes non-
functional, and exaggerated plasma glucose levels result.
As might be expected, mild or moderate intrinsic renal in-
sufficiency in elderly patients hastens this course of
events. Hyperglycemic hyperosmolality also results when
normal or nearly normal compensatory mechanisms are
overwhelmed by an enormous osmotic load, such as in
peritoneal dialysis with a hypertonic solution, administra-
tion of large quantities of hypertonic saline, intravenous
hyperalimentation, nasogastric or intragastric tube feed-
ings without adequate free-water administration, or the
ingestion of large quantities of sucrose-containing bever-
ages. Thus, it is not surprising that approximately 50 per-
cent of patients presenting with hyperglycemic hyperos-
molar coma have no prior history of treatment for diabetes
WI.
Cardiovascular collapse poses the single greatest
threat to patients in hyperosmolar coma. Patients with the
syndrome are always severely hypovolemic (unless renal
failure is severe). Hyperglycemia itself contributes signifi-
cantly to effective extracellular osmolarity so that elevated
concentrations of glucose constitute a major osmotic fac-
tor that retains water (and therefore volume) in the extra-
May 16, 1996
SYMPOSIUM ON DIABETES IN THE ELDERLY-GREENE
cellular space, partly compensating for the reduced
amount of total extracellular sodium that occurs after pro-
longed osmotic diuresis. Thus, hyperglycemia plays an
essential role in preventing vascular collapse in patients
with hyperglycemic dehydration syndrome, and attempts
to rapidly lower the plasma glucose level with insulin
should be deferred until adequate sodium replacement
has occurred.
The basis for central nervous system dysfunction, and
particularly its relationship to plasma osmolarity, is a sub-
ject of considerable debate. Foster [32] concluded that
“the basis for the altered central nervous system function
is almost surely dehydration per se. This is suggested by
the similarity of symptoms in diabetic hyperosmolar coma
and nondiabetic hyperosmolar states.” In contrast,
Winegrad and Morrison [25] comment that “it is now rec-
ognized that coma is not an invariable manifestation, and
while hyperosmolarity is usually present, its role in the
pathogenesis of the disturbances in consciousness that
may occur is still a matter of dispute.” Other potential ex-
planations include altered cerebral perfusion secondary to
either hypovolemia or a hypercoagulable state. In contrast
to ketoacidosis, where depressed global mentation is
prominent but focal neurologic signs are rare, hyperosmo-
lar hyperglycemia is often associated with a focal neuro-
logic deficit, such as hemiplegia or either localized or glo-
bal seizures [26]. Additional neurologic findings include
extensor plantar reflex (Babinski’s), aphasia, homony
mous hemianopia, hemisensory deficit, visual hallucina-
tions, muscle fasciculations, central hyperthermia, and
nystagmus that resolve with treatment of the hyperosmo-
lar hyperglycemia. Seizures, in particular, respond rapidly
to correction of hyperglycemia [26].
Although plasma glucose concentrations generally ex-
ceed 600 to 800 mg/dl [26] during hyperosmolar coma,
the syndrome can occur with a plasma glucose level no
higher than 400 mg/dl [27]. When the plasma glucose
concentration is greater than 800 mg/dl, hypernatremia
with a serum sodium concentration of more than 150
meq/liter is usually present. Plasma glucose values as
high as 4,800 mg/dl and serum sodium values as high as
210 meq/liter have been reported in hyperosmolar coma
[26]. The serum potassium concentration may be high,
low, or normal, but total body potassium is always de-
pleted unless renal failure is severe. The hematocrit is
usually markedly elevated, and a normal hematocrit in
hyperosmolar hyperglycemia is indicative of an underlying
anemia. Hematocrits of more than 90 percent have been
described in the hyperglycemic dehydration syndrome
[26]. Polymorphonuclear leukocytosis is characteristic,
and white blood cell counts are frequently as high as
20,000/mm3, with occasional values in the 50,000/mm3
range. Virtually all patients with the hyperglycemic hyper-
osmolar dehydration syndrome have elevated blood urea
nitrogen and serum creatinine levels at presentation, and
The American Journal of Medicine Volume 90 (suppl 5A) 51
SYMPOSIUM ON DlAbETES IN THE ELDERLY-GREENE

most have c!inically det&table renal impairment following
resolution of the hyperosmolar state [28]. Hybrlipemia
may be marked, usually with a type V pattern or a type I
pattern, which clears rapidly with treatment [28]. Since
marked hypehipemia artificially lowers the serum sodium
concentration, it may confuse the electrolytic evaluation.
Complicating acute and chronic illnesses are the rule
rather than the exception, and their presence may be the
factor that most significantly affects the prognosis of pa-
tients with hyperosmolar hyperglycemia syndrome [28].
An elevated white cell count, hypetthertnia, hypothermia,
and shdck may all be manifestations of the tiyperosmolar
hypdrglycemia syndrome, so the presence of septicemia
or other life-threatening bat&Gal infection6 is difficult to
detect.
Cerebrovascular accidents and cardlogenic shock
occur frequently, but their diagnosis is often masked by
the focal neurologic deficits and hypotension of the hypei-
osmolar conia itself. In older patients and in thdse with
preexisting cardiovascular disease, central venous or pul-
moiiary-arterial hemodynamic rhonitoiing is often indi-
cated. Ttie importance of hemodynamic factors is under-
scored by the obsewation that approximately 33 percent
of the deaths of comatose diabetic patients can be attrib-
uted to cardiovascular or thromboembolic events [28].
There is considerable disagreement regarding the type of
crystalloid that should be administered, but it is $enerally
agreed that replabeinent should be initiated witti either
colloid or isotonic saline If vascular collapse has occurred
[24,25,27,32]. Where& some experts str&s the use of
isotonic saline as the primary initial fluid replacemeht in
most patients with’ hyperosmolar coma [25,27J, oth&s
[24,28,28-30,321 suggest that hypotonic saline is “the
replacement fluid of choice.” The latter authors recoin-
mend that hypotonic saline “should be used as a vehikle
to provide free water as well as volume expansion . . .
when the blood press&e is stabilized or initially in those
patients in whom shock is not a co?sideiation.” Therapy
should be individualized, so that in the presence of severe
hypematremia, for instance, the use of hypotonic saline
might be considered. -It is Important to note that the ma-
jor contrhindication of hypotonic saline in diabetic keto-
acidosis, cerebral edei’na, has never been documentti
in hyperosmolar cdmL [32]. If oliguria persists follow-
ing adequate fluid ~epla&ment, diuretic therapy may
be indicated, sin@ congestive heart failure and/or pul-
monary edema may be masked by the presence of
massive dehydration’ and hypovolemia, and sodium
excretion may be impaired if significant renal disease
is present.

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May IS, 1986 The Amerkan Journal of Modlclne Volume 80 (ruppl SA) 53