Glucose Regulation in Young Adults with Very Low Birth Weight
Petteri Hovi, M.D., Sture Andersson, M.D., Ph.D., Johan G. Eriksson, M.D., Ph.D., Anna-Liisa Järvenpää, M.D., Ph.D., Sonja Strang-Karlsson, M.D., Outi Mäkitie, M.D., Ph.D., and Eero Kajantie, M.D., Ph.D.
ABSTRACT
Background: The association between small size at birth and impaired glucose regulation later in life is well established in persons born at term. Preterm birth with very low birth weight (<1500>Methods: We performed a standard 75-g oral glucose-tolerance test, measuring insulin and glucose concentrations at baseline and at 120 minutes in 163 young adults (age range, 18 to 27 years) with very low birth weight and in 169 subjects who had been born at term and were not small for gestational age. The two groups were similar with regard to age, sex, and birth hospital. We measured blood pressure and serum lipid levels, and in 150 very-low-birth-weight subjects and 136 subjects born at term, we also measured body composition by means of dual-energy x-ray absorptiometry.
Results: As compared with the subjects born at term, the very-low-birth-weight subjects had a 6.7% increase in the 2-hour glucose concentration (95% confidence interval [CI], 0.8 to 12.9), a 16.7% increase in the fasting insulin concentration (95% CI, 4.6 to 30.2), a 40.0% increase in the 2-hour insulin concentration (95% CI, 17.5 to 66.8), an 18.9% increase in the insulin-resistance index determined by homeostatic model assessment (95% CI, 5.7 to 33.7), and an increase of 4.8 mm Hg in systolic blood pressure (95% CI, 2.1 to 7.4). Adjustment for the lower lean body mass in the very-low-birth-weight subjects did not attenuate these relationships.
Conclusions: Young adults with a very low birth weight have higher indexes of insulin resistance and glucose intolerance and higher blood pressure than those born at term.
The full article can be found here.
22 comments:
Here is what Dr. Howard Bauchner wrote in _Journal Watch_ about this study:
"... neonates who weighed 1000 g in the 1960s had a 95% chance of dying, while today they have a 95% chance of surviving. During the past decade, our focus has shifted from survival to understanding the neurocognitive, and more recently, metabolic consequences of prematurity. Whether these data represent a response to the stress of premature birth or the lack of complete in utero organogenesis is unknown. Further, the longer-term consequences of these observations have yet to be detailed."
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And from the editorial that accompanies the NEJM article:
Prematurity and the Legacy of Intrauterine Stress by Julie R. Ingelfinger, M.D.:
"A substantial body of work over the past two decades indicates that
among persons born at term, those with relatively lower birth weights
have a higher relative risk of health problems in early adulthood,
including hypertension, cardiovascular disease, and type 2 diabetes.
The association between low birth weight and an increased risk of
metabolic disorders long after birth has been documented in many
epidemiologic studies as well as in animal models. One concept that
has gained in popularity is that of a "thrifty phenotype," generally
meaning that intrauterine malnutrition leads the fetus to adapt during ongoing development in an attempt to maintain an adequate nutrient supply for the brain. In a fetus challenged by an adverse intrauterine milieu, according to this theory, other organs,including the pancreas and the kidney, are shortchanged and undergo subtle, incompletely delineated alterations during organogenesis. In the case of the pancreas, liver, and muscle, such changes are thought to "reset" the person's metabolism.
According to this theory, when a person who was challenged in fetal
life by maternal malnutrition, infection, or gestational diabetes is faced later with an unlimited supply of food, the risk of excess
weight gain is high. In other words, the fetus challenged in utero reacts with a "predictive adaptive response" that anticipates the postnatal environment. A malnourished fetus will, metabolically
speaking, "expect" to be in a postnatal environment that has limited resources. When the environment is instead generous, overcompensation is likely, with resultant overweight.
Limited evidence suggests altered organogenesis in these infants.
Within the kidney, for example, there appear to be fewer nephrons in persons who had lower birth weights. Since nephrogenesis is usually ongoing until 34 to 36 weeks of age, it probably continues to take
place in premature infants after birth. Thus, a "28-weeker" would
still be making new nephrons for another 8 weeks. Since such an
infant is likely to receive more than one nephrotoxin as a patient in a NICU, these "lifesaving" treatments add potential insults to the developing kidney. Similarly, the developing pancreas of a challenged fetus appears to have a decreased number of beta cells and decreased beta-cell mass. Alterations have also been reported in liver, adipose
tissue, and muscle.
The altered physiology that results long after intrauterine challengewas previously termed "perinatal programming" and has more recently
been framed as the developmental origin of health and disease.
Many systemic alterations have been postulated to explain this
phenomenon: changes in the hypothalamic–pituitary and neuroendocrine axes; changes in the availability and processing of vasoactive substances, such as angiotensin II, which is generated by the renin–angiotensin system; and alterations in the expression of many genes."
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I have so many questions and comments here, I hardly know where to begin. I guess I'll start with the questions:
1)On preemie-child, we recently had a discussion about our children's problems with sweating -- either excessive sweating (the most usual manifestation -- one child's hands seat so badly he cannot hold a pencil) or, in another case, one multiply disabled child has an inability to sweat.
Do we have any MDs reading this blog who would like to comment on why excessive sweating (or inability to sweat) might be a problem of prematurity. Could it have to do with alterations in the hypothalamic-pituitary and neroendocrine axes? Is it a hypothalamus problem from brain damage?
2) I have also heard that preemies are at risk for early Alzheimer's.
Why might this be so?
3) How does "catch-up" growth in early infancy ameliorate or worsen the later metabolic picture?
Thanks for posting this. Very informative.
At the end of Helen's very informative comment she posted some questions. I am posting them below because I didn't want them to be missed.
To the docs out there. I know you are reading this blog, thanks to Site Meter. You are getting an insight into what parents (and former preemies) are experiencing. We all would love to hear your thoughts on this topic and the following questions. I can understand you not wanting to use your real name which is why I allow "anonymous" posting. Please join in!
Here are Helen's questions.
"I have so many questions and comments here, I hardly know where to begin. I guess I'll start with the questions:
1)On preemie-child, we recently had a discussion about our children's problems with sweating -- either excessive sweating (the most usual manifestation -- one child's hands seat so badly he cannot hold a pencil) or, in another case, one multiply disabled child has an inability to sweat.
Do we have any MDs reading this blog who would like to comment on why excessive sweating (or inability to sweat) might be a problem of prematurity. Could it have to do with alterations in the hypothalamic-pituitary and neroendocrine axes? Is it a hypothalamus problem from brain damage?
2) I have also heard that preemies are at risk for early Alzheimer's.
Why might this be so?
3) How does "catch-up" growth in early infancy ameliorate or worsen the later metabolic picture?"
Here are a few of mine...
Why am I seeing more preemies with adrenal issues? My daughter (now 8) was diagnosed with CAH in the NICU, but it was later recanted. Recently I've been seeing more and more preemies with adrenal issues.
Premature Puberty?? Many preemies (especially girls) reach puberty much sooner than their full term peers. One endocrinologist said that it was common among kids with brain damage. But, I've been seeing it happen with preemies who do not have brain abnormalities and/or CP.
Any thoughts??
Stacy
I wanted to add...
Count Paige in as one of the kids who does NOT sweat. I have to watch her very carefully because she gets overheated easily.
"2) I have also heard that preemies are at risk for early Alzheimer's.
Why might this be so?"
The scrambled neuronal migration and diminished grey and white matter volume in former-prematures may--and most likely--causes premature aging of the brain, and, or, an abnormal effect of aging on such maldeveloped brains.
Some alarming symptons were mentioned over on the adult ROP list, but any helpful information apart from symptoms--which first occured and then worsened over a five year period--were refused when asked.
What information is available on the age and gestation of former prematures who develop early Alzheimers disease?
To ex-preemie:
I heard a neonatologist say that preemies had a greater vulnerability to Alzheimer's at a National Perinetal Association conference in 2004 during a question and answer session.
He gave no references and I wasn't able to get to him after the session to ask further questions. I would really like to know if this is just a hypothesis (based on the brain factors you mentioned) or if there has been an actual study.
I have an overly sweaty former 27 weeker here. In fact, she is always excessively warm. She never uses blankets while sleeping and refuses to wear a coat most of the time. She is never cold.
She is also a failure to thrive kid. We are always trying to find ways to pack on the pounds. No matter how much she eats, her growth curve never changes. Thankfully, her growth has stabilized though...always in the 3rd percentile for height and weight. We found success using a drug called cyproheptadine, which is actually a antihistamine but was found to increase the appetite. Our pedi GI swears by it in kids who eat an adequate amount of calories to gain, but don't seem to be able to appropriately use those calories. The drug has been very effective for my kiddo.
Jen, mom of Grace (former 34 weeker) and Meghan (former 27 weeker)
My own thoughts about excessive sweating are that it relates to low basal nitric oxide. My research indicates that part of what sets the basal NO level is autotrophic ammonia oxidizing bacteria living on the external skinn and metabolizing ammonia in sweat into nitrite and nitric oxide.
Everytime I see excessive sweating, I think "not enough nitric oxide".
Nitric oxide is one of the things that initiates mitochondria biogenesis. If you don't have enough mitochondria you will be in a "hypermetabolic state". That is, your basal metabolism will consume more calories. It isn't that your body is doing more stuff, rather with fewer mitochondria the efficiency of ATP production is reduced, so you need more substrate (food and oxygen) to make the same ATP.
How might one increase low basal NO?
Does sildenafil have a role to play here?
How does skin bacteria increase NO production?
Dave (daedalus2u),
Interesting. I've done so much reading up on mitochondria because it was thought that my daughter may have a mito issue. We never went through with the fresh muscle biopsy to find out-she had recovered from her extreme fatigue by then.
I'm just wondering.. if low NO would help, are mito patients instructed on this?? Besides on your website, this is the first I'm hearing about it in relation to the mitochondria.
Stacy
More questions for daedalus2u,
How might prematurity alter NO in later life?
Does menopause (eg, hot flashes) or general "heat intolerance" reflect NO problems?
Any remedies?
The only ways that I know how to increase basal NO are with my bacteria, meditation, and by eating foods rich in nitrate (green leafy vegetables have about 0.1% nitrate). They have different effects.
My method for raising NO level is not generally accepted. The existance and importance of a basal level of NO is not widely accepted by the NO research community. There are a few of us who do recognize it. I am in contact with most of them.
There is no generally recognized way of increasing systemic NO levels, although there is intense research in this area. I think that pharmacological methods are not going to work because of the complexity of NO physiology. NO is extremely well regulated. It is very difficult to artifically perturb it, and extremely difficult to perturb it without side effects. NO regulates thousands of pathways. It is inconceivable that we could somehow artifically regulate thousands of pathways.
The importance of NO on mitochondria biogenesis is fairly new, and is not at all recognized by clinicians, nor by many researchers either.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16825426&query_hl=12&itool=pubmed_docsum
"Stress" is a low NO state. If you are under stress for a long time, it can lower NO levels during the period of mitochondria turnover. Low NO during mitochondria turnover reduces the number. Few mitochondria can produce the same ATP as many, but only by increasing the membrane potential, which increases superoxide levels, which reduces NO levels. I think you can get into a metabolic state where there are no excess mitochondria. You are "fine", unless you increase your ATP consumption, which you are unable to increase because you don't have more mitochondria to do so. I think this is what is known as chronic fatigue.
Sildenafil works by inhibiting the phophodiesterase (PDE5), which destroys cGMP produced by sGC when activated by NO. cGMP relaxes smooth muscle which is what causes erectile tissue to become engorged. More cGMP is going to feedback inhibit nitric oxide synthase so less NO will be produced. In obstructive sleep apnea, sildenafil actually makes it worse. I think by lowering NO levels and reducing effects of NO not mediated through cGMP such as breathing initiation (activated by high NO).
NO does regulate estrogen production by inhibiting the cytochrome P450 enzyme that makes it. There is feedback where estrogen activates the estrogen receptor, activates NOS, and the NO activates down stream things. There is some thought that it is NO from the estrogen receptor that protects premenapausal women from heart disease.
Heat intolerance is likely to be a low NO state.
This is somewhat off topic (not necessarily prematurity related) but can you comment on on the presence of the genetic variation G894T of the eNOS gene?
A few more questions (I'll have many more soon, I feel sure):
what is your bacteria? Is it commercially available?
How does it increase NO systemically?
Which green veggies do you specifically recommend?
Does D-Ribose supplementation have any place in this picture?
What are your thoughts on acetyl-L-carnitine and alpha lipoic acid supplementation?
I have no idea what G894T would do by what mechanism. The focus of my work is only on NO from "my" bacteria and the influence of basal NO on NO mediated pathways.
I suspect that what ever G894T does do, that it would be worse under conditions of low NO. There have been eNOS knock-out animals produced (and nNOS and iNOS and even triple KOs). It is surprising to me that they are viable. I think that simply shows how redundant and robust physiology is, that there are back-up systems. I suspect that is what a lot of the NO from non-NOS systems participates in.
Thank heaven for redundancy!
My bacteria are not available yet.
They are autotrophic ammonia oxidizing bacteria. The only way they get organic carbon is by fixing CO2. They are incapable of growth on any media used for isolating pathogens. They have no virulence factors, excrete no toxins, are incapable of digesting any animal tissues. I think they are incapable of causing infection even in immunocompromised individuals.
Green leafy vegetables have the highest nitrate levels, lettuce, spinach are about the same. Too much nitrate is bad due to the potential for methemoglobinemia (aka blue baby). That is likely not an issue for anyone over a year old (unless you have methemoblobin reductase deficiency).
I think that most supplements are completely unnecessary (in the absence of deficiencies) and may be harmful. There was a recent JAMA article that showed that supplemental antioxidants actually increased mortality.
Thanks! This has been enlightening.
I'm still curious as to how a skin bacteria can alter systemic NO levels.
Also, what would you say about the NO issues in an extremely underweight preemie who (in his 20s, despite restrictive diet and exercise (4 miles walking/day) has become badly overweight? He has been an excessive "sweater" throughout his life?
These bacteria on the skin metabolize ammonia in sweat into nitrite and nitric oxide. Nitrite is well absorbed through the skin, and so is NO. In the body, the normal "sink" for NO, is hemoglobin, that is hemoglobin destroys NO at near diffusion limited kinetics. The external skin is free from hemoglobin, it gets O2 from the external air.
I don't know the details of how NO and nitrite from these bacteria has all these systemic effects, but it does.
I think there is a mechanism where a person with insufficient mitochondria (especially in the liver) could become obese. Cells have 2 ways of generating ATP, either via oxidation (from mitochondria), or from glycolysis (which converts glucose into lactate and makes ATP). Glycolysis makes only 1/19 the amount of ATP from a molecule of glucose that oxidation does, so it takes 19 times more glucose to supply ATP via glycolysis than from oxidation. If you shift 5% of ATP production from mitochondria to glycolysis, it takes twice as much glucose to supply it. I think this is where the hyperglycemia of the metabolic syndrome comes from.
The glucose is converted to lactate, which every cell can also use as a substrate for ATP production, but only by oxidation in mitochondria. Normally, lactate is recycled by the liver and kidneys into glucose, via the Cori cycle through glucogenesis. But that takes mitochondria to do. If there are not enough mitochondria in the liver and kidneys, the lactate can't be recycled. The body doesn't let lactate accumulate, it can't be excreted in the kidneys, where does it go? I suspect it is converted into fat. First depot fat, then ectopic fat (as things get worse).
The glocuse concentration that is important, is the concentration at each individuals cell. Most cells are not in contact with blood, they are in the extravascular space which is only perfused by plasma. The glucose and insulin levels there are much more difficult to measure, and must obviously be lower than in the blood (due to consumption by intervening cells). If the body is trying to supply 2x as much glucose to those cells farthest from a capillary, how would the body do it? Obviously, glucose concentration in the blood has to go up. Glucose transport into cells is active, that is it is only mediated by glucose transporters, not by passive diffusion. If a cell needs more glucose, it must express more glucose transporters on its surface. One of the things that causes expression of glucose transporters is insulin. Insulin causes more glucose transporters to be on the cell's surface and increases glucose import. But a cell has only a certain amount of surface area for those transporters to fit in, so obviously, there is a limit.
Exercise per se, doesn't increase endurance. It is the increased mitochondria number produced during the resting period afterward that does that. That involves NO.
Recently I've been seeing more and more preemies with adrenal issues.
I guess I am a rare bird. Born 8 weeks premature in 1956 I survived. I have had all the metabolic issues you cite as well as epilepsy. All of my issues are completely controlled by living a low carb lifestyle. So your hypothesis that we premies are born with systems adapted for malnutrition/low glucose makes perfect sense.
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