〔Review

Vol.4 No.1 Article〕 Shyang-Rong Shih et al Taiwan Geriatrics & Gerontology

The Effects of Aging on Glucose Metabolism

Shyang-Rong Shih1, Chin-Hsiao Tseng1,2,3,4

Abstract

Type 2 diabetes mellitus is the most common chronic metabolic disease/disorder in

the elderly. The prevalence and incidence of impaired glucose tolerance and diabetes
mellitus increase with aging. In Taiwan, the prevalence of diabetes mellitus increases
with age and is approximately 20% in those aged 65 years or older. The incidence of
diabetes mellitus is also increasing in Taiwan. In an epidemiologic study which showed
an average incidence of 9.3 per 100,000 population in those aged <35 and 725.8 per
100,000 population in those aged ≥65 years. Responsible mechanisms of age-related
glucose intolerance include decreased insulin sensitivity and decreased β-cell function.
Decreased β-cell function may be related to glucotoxicity and mitochondrial dysfunction.
Insulin resistance is related to mitochondrial dysfunction and increased intramyocytic
triglyceride. Decreased number of insulin receptors, decreased AMP-activated protein
kinase (AMPK) activity, decreased adiponectin and increased leptin are other postulated
factors. Further studies are necessary to examine these hypotheses, to find out the key
afflicting factors, and to work up as the target.
(Taiwan Geriatrics & Gerontology 2009; 4(1): 27-38)

Key words: aging, glucose intolerance, diabetes mellitus, insulin sensitivity,

insulin resistance

1
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital
Yun-Lin Branch, Yun-Lin, Taiwan.
2
Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
3
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital,
Taipei, Taiwan.
4
Department of Medical Research and Development, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin,
Taiwan.
Correspondence to: Chin-Hsiao Tseng, No. 7 Chung-Shan South Road, Taipei, Taiwan. Department of Internal
Medicine, National Taiwan University Hospital
E-mail: ccktsh@ms6.hinet.net

27
台灣老誌 The Effects of Aging on Glucose Metabolism
Introduction
Type 2 diabetes mellitus (DM) is the
most common chronic metabolic disease in
the elderly [1]. The prevalence and incidence
of impaired glucose tolerance and DM
increase with aging [2]. The incidence of
new cases is 10 times greater for the elderly
than for persons aged under 45 in one study
[3]. In the Belgian Elderly Diabetes Survey,
the prevalence of impaired fasting glucose
(IFG) is approximately 4%, and of DM
10%, most of which (80%) was undiagnosed
[2]. DM shows little gender preference
although it becomes slightly more frequent
in women with advancing age [4].
In Taiwan, the prevalence and
incidence of diabetes mellitus show a
similar association with aging [5,6]. In a
national survey of 6,600 residents in 2002,
the age-standardized (to the World Health
Organization year 2000 population)
prevalence was 6.6% (unpublished data).
The prevalence increased with age and was
approximately 20% in residents aged ≥65
years (unpublished data). As for the
incidence of type 2 DM in Taiwan, it had
been observed to sustain an upward trend
during the period of 1992- 1996 [5]. The
average yearly incidence during that
period was 187.1 per 100,000 population
for men and 218.4 per 100,000 population
for women. Age is an important
28
第 4 卷第 1 期
determinant for the incidence of DM. Peak
incidence was noted at the age of 55-64
years and decreased slightly after the age
of 65 years [5]. In both sexes, the incidence
(per 100,000 population) read 9.3, 144.9,
547.2, 937.0 and 725.8 for those aged <35
years, 35-44, 45-54, 55-64 and ≥65 years,
respectively [5].
Incidence of cardiovascular and
peripheral vascular complications and the
rate of mortality from cardiovascular
causes are twice greater for elderly DM
patients than for their non-DM counterparts
[7]. Furthermore, elderly diabetic patients
face a higher risk of developing hypertension
[8-11], and macro- and micro-vascular
complications [12-19]; they also suffer a
higher mortality rate than younger diabetic
patients [20,21]. In a 10-year prospective
population study of 406 subjects, the
respective ten-year total mortality of
subjects with normal glucose tolerance and
that of subjects with DM were 49% and
72% in men, and 24% and 65% in women
[22]; and the respective ten-year
cardiovascular mortality rates for the normal
and DM groups were 19% and 44% in
men, and 8% and 35% in women [22].
Excess mortality was observed in both sexes
when DM existed at 70 years of age, and in
men when impaired glucose tolerance
(IGT) existed at this age. The excess
mortality in men could solely, and in
women partly, be explained by
Vol.4 No.1 Shyang-Rong Shih et al Taiwan Geriatrics & Gerontology

cardiovascular causes [22]. In another
study of the burden of mortality of diabetes
in the year 2000, 29% of all deaths in DM
patients older than 64 years were attributable
to diabetes [23]. DM accounted respectively
for 5.6% and 8.2% of all-cause deaths
among male and female residents older
than 64 years in Southeast Asia [23]. The
relative risk of dying for 60-79 year-old
individuals with diabetes is 2.25 times
greater than for the elderly people without
diabetes [23].
In this paper we will review the current
knowledge about the effects of aging on
glucose metabolism.
Rises in Fasting and Postprandial
Blood Glucose
Glucose tolerance tends to be markedly
impaired in the elderly. Most studies have
revealed impaired glucose metabolism
among the elderly with rises in fasting and
especially postprandial blood glucose
levels that directly correlate with age [24].
Fasting blood glucose increases by 1 to 2
mg/dL and postprandial blood glucose up
to 15 mg/dL per decade in age [24]. Most
diabetic patients belong to the category of
type 2 DM, especially when diabetes is
diagnosed in the elderly [2]. Responsible
mechanisms of age-related glucose
intolerance include: 1) decreased insulin
sensitivity, either from receptor
abnormalities, decreased exercise, or
increased adiposity; 2) decreased β-cell
function; and 3) altered dietary habits and
decreased insulin-to-glucose ratio [24].
Other factors that can adversely affect
glucose tolerance in aging include drug
use, interfering conditions from associated
diseases, and other stressful conditions
commonly encountered during acute
hospitalization [2] (Table 1).

Table 1 Potential Mechanisms Responsible for Age-related Glucose Intolerance

Possible mechanism Possible contributing factors
Intrinsic factors
Impaired β-cell function β-cell glucotoxicity
Age-related mitochondrial dysfunction
Decreased insulin sensitivity Decreased insulin receptor number
Age-related mitochondrial dysfunction
Increased intramyocellular triglyceride
Decreased AMPK activity
Decreased adiponectin
Increased leptin
Extrinsic factors Decreased exercise level
Increased adiposity
Drugs
Associated diseases or other stressful conditions

29
台灣老誌 The Effects of Aging on Glucose Metabolism
Impaired β-cell Function
Reductions in both early and late
phases of insulin release are well documented
in the elderly with type 2 DM [2,24].
In the Belgian Elderly Diabetes
survey, most participants had normal or
higher than normal insulin sensitivity and
normal or moderately decreased β-cell
function, whereas participants with IFG or
DM had significantly decreased β-cell
function and insulin sensitivity [2].
Secretory defects in β-cell seem to be a
common occurrence in the elderly.
Meneilly et al. compared healthy lean
and obese elderly with type 2 DM lean and
obese elderly [26]. Lean elderly type 2 DM
patients showed a profound impairment in
glucose-induced insulin release but mild
resistance to insulin-mediated glucose
disposal [26]. It was suggested that decreased
β-cell function was attributed to the toxic
effects of chronic hyperglycemia, the so
called β-cell glucotoxicity [25]. Adversely,
obese elderly type 2 DM patients reported
adequate circulating insulin but marked
resistance to insulin-mediated glucose
disposal in the study [26]. Other studies
further suggest that fasting hyperinsulinemia,
impaired first- and second-phase insulin
release, increased fasting hepatic glucose
output, and resistance to insulin-mediated
glucose disposal are all involved in the
30
第 4 卷第 1 期
alteration in glucose metabolism in obese
middle-aged patients with type 2 DM [27,
28]. It is reasonable that since impaired
β-cell function is observed in obese
middle-aged patients with type 2 DM, it
must play some role in obese elderly DM
patients. Mitochondrial energy metabolism
plays a critical role in glucose-induced
insulin secretion [29]. Age-associated
reduction in mitochondrial function has
been demonstrated to affect insulin
sensitivity [29]. Whether it may also affect
insulin secretion forms a subject deserving
further studies.
Decreased Insulin Sensitivity
Evidence of decrease in insulin sensitivity
Although several studies suggested
normal or higher than normal insulin
sensitivity in the elderly [2], most studies
showed the transition from the normal
state to overt type 2 DM in aging was
typically characterized by deterioration in
glucose tolerance [1, 29]. Petersen et al.
studied healthy elderly and young people
matched for lean body mass and fat mass
[29]. The elderly subjects had slightly
higher plasma glucose concentration and
significantly higher plasma insulin
concentration during the test of oral glucose
tolerance. Basal glucose production rates
were similar while glucose infusion rates
Vol.4 No.1 Shyang-Rong Shih
required to maintain euglycemia and
insulin-stimulated rates of peripheral
glucose uptake were about 40% lower in
the elderly subjects during hyperinsulinemic-
euglycemic clamp [29]. These suggest that
the elderly are relatively insulin resistant.
Alterations of insulin receptors and
postreceptor levels
Bolinder et al. used subcutaneous
adipose tissue from healthy subjects to
study the influence of aging on insulin
action [30]. They found that insulin
binding per cell in the older group was
50% lower than the one in the younger
group, essentially owing to a decrease in
the number of insulin receptors [30].
Insulin sensitivity, as reflected by the
degree of antilipolysis and stimulation of
glucose oxidation, was 10 to 20 times
lower in the older subjects. Basal lipolysis
and the maximum anti-lipolysis effect of
insulin were similar in the young and the
old groups. The basal rate of glucose
oxidation in the older subjects was less
than one-half that for the young group, and
the maximum level of insulin-induced
glucose oxidation was lower by about
75%. Age was significantly and negatively
correlated with the number of insulin
14
receptors, basal production of CO2, and
the maximal level of insulin-induced
glucose oxidation [30]. Aging is accompanied
31
et al Taiwan Geriatrics & Gerontology
by impairment of the action of insulin on
target cells, owing to alterations at both
the receptor and the postreceptor levels
[30].
Intramyocellular triglycerides, mitochondria
and insulin resistance
Intramuscular fat and hepatic steatosis
are strongly related to insulin resistance
[31, 32]. Hydrolysis of triglycerides
located within the myocytes is postulated to
trigger an increase in long-chain acyl CoA
diacylglycerol, which in turn can activate
protein kinase C, thereby impairing insulin
signaling [33, 34]. This further leads to
reduced insulin-stimulated muscle glucose
transport activity, reduced glycogen synthesis
in muscle, and impaired suppression of
glucose production by insulin in the liver
[35, 36]. Sinha et al. used 1H nuclear
magnetic resonance spectroscopy to study
the intramyocellular (IMCL) and
extramyocellular (EMCL) triglycerides of
the soleus muscle [37]. They found that
both the IMCL and EMCL triglycerides
were significantly greater in the obese
adolescents than in the lean control
subjects. There was a strong inverse
correlation between IMCL triglycerides
and insulin sensitivity, which persisted
after adjusting for percent total body fat
and abdominal subcutaneous fat mass but
not when adjusting for visceral fat. IMCL
台灣老誌 The Effects of Aging on Glucose Metabolism
and EMCL triglycerides are significantly
associated with visceral fat mass, implying
that intracellular lipid accumulation might
be a result of an increased flux of free fatty
acids into muscle from the enlarged
visceral adipose depot [37].
According to the study of Petersen et
al., increased fat accumulation in muscle
and liver tissue was detected with nuclear
magnetic resonance (NMR) in the elderly,
and insulin resistance was suggested by
hyperinsulinemic-euglycemic clamp [29].
Hepatic insulin resistance, however, was
not observed during the clamp. Another
study also showed that hepatic glucose
output is similar in healthy or DM and lean
or obese old people [26]. These studies
together suggest that age-associated insulin
resistance is mainly attributable to reduced
insulin-stimulated muscle glucose
metabolism but not hepatic insulin
resistance [26, 29].
Age-associated reductions in
mitochondrial number and function were
demonstrated, possibly resulted from
age-associated accumulation of mutations
in control sites for mitochondrial DNA
replication [38]. In vitro, decrease of state
II mitochondrial respiration was detected
in isolated mitochondria of elderly people
[39]. In vivo, an approximately 40%
reduction in mitochondrial oxidation
assessed by 13C NMR and phosphorylation
31
activity assessed by P NMR in skeletal
32
第 4 卷第 1 期
muscle were also observed in the elderly
[29]. This may be a contributing factor to
the increased content of triglycerides in
muscle and liver.
The AMP-activated protein kinase (AMPK)
AMPK, as a chief regulator of
whole-body energy balance [40], plays a
crucial role in regulating mitochondrial
biogenesis and fatty-acid oxidation. Once
activated in skeletal muscle, AMPK exerts
control in part by regulating fatty-acid
oxidation through the phosphorylation of
acetyl-CoA carboxylase 2 and mitochondrial
biogenesis through increasing the expression
of proteins vital for proper mitochondrial
functions such as citrate synthase and
succinate dehydrogenase [41, 42]. In an
animal study, acute stimulation of AMPK
activity by 5-aminoimidazole-4- carboxamide-
1-β-D-ribofuranoside and exercise was
blunted in skeletal muscle of old rats.
Mitochondrial biogenesis in response to
chronic activation of AMPK with
β-guanidinopropionic acid feeding was
also diminished in old rats. These results
suggest that aging-associated reductions in
AMPK activity may be a major contributing
factor in the reduced mitochondrial function
and dysregulated intracellular lipid
metabolism associated with aging [43].
Leptin and adiponectin
Vol.4 No.1 Shyang-Rong Shih
Leptin is a peptide synthesized mainly
by white adipose tissue and positively
related to insulin resistance independent of
the degree of adiposity [44]. Adiponectin
is a protein produced by adipocytes and
inversely related to the degree of adiposity
and insulin resistance [45, 46]. Decreased
adiponectin levels is a risk factor of type 2
DM in the general population [47, 48]. In a
study focusing on elderly people, both
fasting insulin and homeostasis model
assessment of insulin resistance (HOMA)
showed significant positive correlation
with leptin and negative correlation with
adiponectin in elderly men and women
[49]. Leptin and adiponectin alone explained
up to 38% of HOMA variance in multiple
linear regression analysis [49]. Leptin and
adiponectin are also strictly related to
insulin resistance independent of body fat
and body fat distribution in the elderly
people as in the general population [49]
Conclusions
Prevalence of impaired glucose
metabolism among the elderly is high [2].
Possible responsible mechanisms include
decreased β-cell function and increased
insulin resistance [2]. Decreased β-cell
function may be related to glucotoxicity
and mitochondrial dysfunction while
insulin resistance is associated with
mitochondrial dysfunction and increased
33
et al Taiwan Geriatrics & Gerontology
IMCL triglycerides [29]. Further studies
are necessary to confirm the above
postulations and perhaps to work up for
the target therapy.
Acknowledgements
The authors would like to thank the
following institutes for their continuous
support on the epidemiologic studies of
diabetes mellitus and arsenic-related health
hazards: the Department of Health
(DOH89-TD-1035; DOH97-TD-D-113-
97009), the National Taiwan University
Hospital Yun-Lin Branch
(NTUHYL96.G001) and the National
Science Council
(NSC-86-2314-B-002-326,
NSC-87-2314-B-002-245,
NSC88-2621-B-002-030,
NSC89-2320-B002-125,
NSC-90-2320-B-002-197,
NSC-92-2320-B-002-156,
NSC-93-2320-B-002-071,
NSC-94-2314-B-002-142,
NSC-95-2314-B-002-311 and
NSC-96-2314-B-002-061-MY2), Taiwan.
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〔綜論〕

老化對葡萄糖代謝的影響

施翔蓉 1 曾慶孝 1,2,3

摘 要

第 2 型糖尿病是老年人最常見的慢性新陳代謝性疾病。葡萄糖失耐症
和糖尿病的盛行率和發生率皆隨著年齡的增加而上升。在台灣的流行病
學研究中發現，糖尿病的盛行率隨年齡增加而上升，65 歲老人糖尿病盛
行率約為 20%；糖尿病發生率在小於 35 歲民眾約為每年每十萬人口中有
9.3 人，在 65 歲以上民眾約為每年每十萬人口中有 725.8 人。導致年齡相
關的葡萄糖耐受性不佳原因包括了 β 細胞功能變差與胰島素敏感性下
降。β 細胞功能變差的原因可能與葡萄糖毒性和粒線體功能障礙相關，而
粒線體功能障礙可能與老化引起之控制粒線體複製的基因突變有關。胰
島素敏感性下降的原因可能與粒線體功能障礙和肌肉三酸甘油酯增加有
關；肌細胞中三酸甘油酯的水解間接地可能會活化蛋白分解酶 C (protein
kinase C)，進而影響胰島素下游訊息的傳遞，即降低胰島素敏感性。其他
可 能 的 相 關 因 子 包 括 胰 島 素 受 器 數 量 減 少 、 AMP- 刺 激 蛋 白 酶
(AMP-activated protein kinase, AMPK)活性減低、脂締素(adiponectin)減少
和瘦素(leptin)增加。但這些致病機轉都還需要進一步研究來證實。找出
關鍵的影響因子，才能發展出有效的治療方式。
（ 台灣老年醫學暨老年學雜誌 2009；4(1)：27-38）

關鍵詞： 老化、葡萄糖耐性不良、糖尿病、胰島素敏感性、胰島素阻抗性

1
國立台灣大學附設醫院內科部、2 國立台灣大學醫學院內科、3 臺大醫院雲林分院內科部暨醫學研究發展部
通訊作者：曾慶孝
通訊處：台北市中山南路 7 號台大醫院內科部
E-mail: ccktsh@ms6.hinet.net

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