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Leptin stimulates fatty-acid oxidation by activating AMP-activated
protein kinase.
Leptin is a hormone secreted by adipocytes that plays a pivotal role in
regulating food intake, energy expenditure and neuroendocrine function.
Leptin stimulates the oxidation of fatty acids and the uptake of glucose,
and prevents the accumulation of lipids in nonadipose tissues, which can
lead to functional impairments known as "lipotoxicity". The signalling
pathways that mediate the metabolic effects of leptin remain undefined.
The 5'-AMP-activated protein kinase (AMPK) potently stimulates fatty-acid
oxidation in muscle by inhibiting the activity of acetyl coenzyme A carboxylase
(ACC). AMPK is a heterotrimeric enzyme that is conserved from yeast to
humans and functions as a 'fuel gauge' to monitor the status of cellular
energy. Here we show that leptin selectively stimulates phosphorylation
and activation of the alpha2 catalytic subunit of AMPK (alpha2 AMPK) in
skeletal muscle, thus establishing a previously unknown signalling pathway
for leptin. Early activation of AMPK occurs by leptin acting directly on
muscle, whereas later activation depends on leptin functioning through
the hypothalamic-sympathetic nervous system axis. In parallel with its
activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating
the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits
the phosphorylation of ACC stimulated by leptin. Our data identify AMPK
as a principal mediator of the effects of leptin on fatty-acid metabolism
in muscle.
Nature. 2002 Jan 17;415(6869):339-43
Can correction of sub-optimal coenzyme Q status improve beta-cell
function in type II diabetics?
A stimulus to mitochondrial respiratory activity is a crucial component
of the signal transduction mechanism whereby increased plasma glucose evokes
insulin secretion by beta-cells. Efficient function of the glycerol-3-phosphate
shuttle is important in this regard, and the rate-limiting enzyme in this
shuttle--the mitochondrial glycerol-3-phosphate dehydrogenase (G3PD)--is
underexpressed in the beta cells of human type II diabetics as well of
rodents that are models for this disorder. Suboptimal tissue levels of
coenzyme Q10 (CoQ) could be expected to further impair G3PD activity. Clinical
reports from Japan suggest that supplemental CoQ may often improve beta-cell
function and glycemic control in type II diabetics. Thus, it is proposed
that correction of suboptimal CoQ status, by aiding the efficiency of G3PD
and of respiratory chain function, will improve the glucose-stimulated
insulin secretion of diabetic beta-cells.
Med Hypotheses. 1999 May;52(5):397-400
Beneficial effects of antioxidants in diabetes: possible protection
of pancreatic beta-cells against glucose toxicity.
Oxidative stress is produced under diabetic conditions and possibly causes
various forms of tissue damage in patients with diabetes. The aim of this
study was to examine the involvement of oxidative stress in the progression
of pancreatic beta-cell dysfunction in type 2 diabetes and to evaluate
the potential usefulness of antioxidants in the treatment of type 2 diabetes.
We used diabetic C57BL/KsJ-db/db mice, in whom antioxidant treatment (N-acetyl-L-cysteine
[NAC], vitamins C plus E, or both) was started at 6 weeks of age; its effects
were evaluated at 10 and 16 weeks of age. According to an intraperitoneal
glucose tolerance test, the treatment with NAC retained glucose-stimulated
insulin secretion and moderately decreased blood glucose levels. Vitamins
C and E were not effective when used alone but slightly effective when
used in combination with NAC. No effect on insulin secretion was observed
when the same set of antioxidants was given to nondiabetic control mice.
Histologic analyses of the pancreases revealed that the beta-cell mass
was significantly larger in the diabetic mice treated with the antioxidants
than in the untreated mice. As a possible cause, the antioxidant treatment
suppressed apoptosis in beta-cells without changing the rate of beta-cell
proliferation, supporting the hypothesis that in chronic hyperglycemia,
apoptosis induced by oxidative stress causes reduction of beta-cell mass.
The antioxidant treatment also preserved the amounts of insulin content
and insulin mRNA, making the extent of insulin degranulation less evident.
Furthermore, expression of pancreatic and duodenal homeobox factor-1 (PDX-1),
a beta-cell-specific transcription factor, was more clearly visible in
the nuclei of islet cells after the antioxidant treatment. In conclusion,
our observations indicate that antioxidant treatment can exert beneficial
effects in diabetes, with preservation of in vivo beta-cell function. This
finding suggests a potential usefulness of antioxidants for treating diabetes
and provides further support for the implication of oxidative stress in
beta-cell dysfunction in diabetes.
Diabetes. 1999 Dec;48(12):2398-406
A prospective study of exercise and incidence of diabetes
among US male physicians.
OBJECTIVE--To examine prospectively the association between regular exercise
and the subsequent development of non-insulin-dependent diabetes mellitus
(NIDDM). DESIGN--Prospective cohort study including 5 years of follow-up.
PARTICIPANTS--21,271 US male physicians participating in the Physicians'
Health Study, aged 40 to 84 years and free of diagnosed diabetes mellitus,
myocardial infarction, cerebrovascular disease, and cancer at baseline.
Morbidity follow-up was 99.7% complete. MAIN OUTCOME MEASURE--Incidence
of NIDDM. RESULTS--At baseline, information was obtained about frequency
of vigorous exercise and other risk indicators. During 105,141 person-years
of follow-up, 285 new cases of NIDDM were reported. The age-adjusted incidence
of NIDDM ranged from 369 cases per 100,000 person-years in men who engaged
in vigorous exercise less than once weekly to 214 cases per 100,000 person-years
in those exercising at least five times per week (P, trend, less than .001).
Men who exercised at least once per week had an age-adjusted relative risk
(RR) of NIDDM of 0.64 (95% Cl, 0.51 to 0.82; P = .0003) compared with those
who exercised less frequently. The age-adjusted RR of NIDDM decreased with
increasing frequency of exercise: 0.77 for once weekly, 0.62 for two to
four times per week, and 0.58 for five or more times per week (P, trend,
.0002). A significant reduction in risk of NIDDM persisted after adjustment
for both age and body-mass index: RR, 0.71 (95% Cl, 0.56 to 0.91; P = .006)
for at least once per week compared with less than once weekly, and P,
trend, .009, for increasing frequency of exercise. Further control for
smoking, hypertension, and other coronary risk factors did not materially
alter these associations. The inverse relation of exercise to risk of NIDDM
was particularly pronounced among overweight men. CONCLUSIONS--Exercise
appears to reduce the development of NIDDM even after adjusting for body-mass
index. Increased physical activity may be a promising approach to the primary
prevention of NIDDM.
JAMA. 1992 Jul 1;268(1):63-7
Physical activity and incidence of non-insulin-dependent diabetes
mellitus in women.
The potential role of physical activity in the primary prevention
of non-insulin-dependent diabetes mellitus (NIDDM) is largely unknown.
We examined the association between regular vigorous exercise and the
subsequent incidence of NIDDM in a prospective cohort of 87,253 US women
aged 34-59 years and free of diagnosed diabetes, cardiovascular disease,
and cancer in 1980. During 8 years of follow-up, we confirmed 1303 cases
of NIDDM. Women who engaged in vigorous exercise at least once per week
had an age-adjusted relative risk (RR) of NIDDM of 0.67 (p less than
0.0001) compared with women who did not exercise weekly. After adjustment
for body-mass index, the reduction in risk was attenuated but remained
statistically significant (RR = 0.84, p = 0.005). When analysis was
restricted to the first 2 years after ascertainment of physical activity
level and to symptomatic NIDDM as the outcome, age-adjusted RR of those
who exercised was 0.5, and age and body-mass index adjusted RR was 0.69.
Among women who exercised at least once per week, there was no clear
dose-response gradient according to frequency of exercise. Family history
of diabetes did not modify the effect of exercise, and risk reduction
with exercise was evident among both obese and nonobese women. Multivariate
adjustments for age, body-mass index, family history of diabetes, and
other variables did not alter the reduced risk found with exercise.
Our results indicate that physical activity may be a promising approach
to the primary prevention of NIDDM.
Lancet. 1991 Sep 28;338(8770):774-8
Relationship between acute insulin response and vitamin K
intake in healthy young male volunteers.
To evaluate the effects of vitamin K (VK) on pancreatic function, especially
on acute insulin response, 25 healthy young male volunteers were given
an oral load of 75 g of glucose, and their mean daily VK intake was estimated
by a one-week food check list. After excluding low (<20) and high (> or
=25) body mass index (BMI) subjects, the remaining 16 participants were
divided into three semi-equal groups according to VK intake. Blood VK status
of the low VK intake group tended to be poorer than that of the high intake
group (median of 5 samples: prothrombin time; 12.5 vs 12.2s and protein-induced
VK absence-factor-II; 23 vs 15 mAU/ml), but fasting plasma glucose status
was not markedly different between both groups: [plasma glucose (PG); 87
vs 86 mg/dl, immunoreactive insulin (IRI); 6.7 vs 5.3 microU/ml, HbA1c;
4.8 vs 4.9%]. However, at 30 min after glucose loading, PG of the low VK
intake group tended to be higher than those of the high intake group (160
vs 145 mg/dl) and IRI was lower (36.1 vs 52.3 microU/ml). Insulinogenic
index (incremental IRI/incremental PG, 0-30 min) of the low VK intake group
was significantly lower than that of the high intake group (0.4 vs 0.9).
These results suggested that VK may play an important role on the acute
insulin response in glucose tolerance.
Diabetes Nutr Metab. 1999 Feb;12(1):37-41
Salmon calcitonin - a potent inhibitor of food intake
in states of impaired leptin signalling in laboratory rodents.
To compare the anorectic effectiveness of leptin and the amylin analogue
salmon calcitonin (sCT), rodents were treated on 1 day with subcutaneous
injections. In chow-fed C57Bl/6J mice, leptin and sCT reduced energy intake
and acted additively. After C57Bl/6J mice had become leptin-resistant on
being fed chocolate as a palatable high-caloric supplement to chow, their
sCT-induced decrease in energy intake was more pronounced than in chow-fed
mice with differential changes in the intake of chocolate (strong reduction)
and chow (slight increase). Dose-response relationships for sCT-induced
reductions in energy intake were analysed in chow-fed C57Bl/6J mice and
two obese strains, ob/ob mice and melanocortin-4 receptor knockout (MC4-r-KO)
mice, as well as in wild-type and fatty (fa/fa) rats. Compared to C57Bl/6J
mice, reduction in food intake induced by sCT was attenuated in MC4-r-KO
mice, and nearly absent in ob/ob mice, over the dose range investigated.
Compared to C57Bl/6J mice, wild-type rats responded more sensitively to
sCT and its efficiency was only slightly reduced in fatty (fa/fa) rats.
Thus, while genetically induced failures of leptin signalling reduce the
action of sCT, it effectively inhibits the intake of a palatable, high
fat-high sugar diet even in states of diet-induced obesity with functional
leptin resistance.
J Physiol. 2002 Jun 15;541(Pt 3):1041-8 |