Slow Wave Sleep, Diabetes and Depression

Chris Ballas, M.D.
Friday, January 25, 2008

The issue with poor sleep is actually poor slow wave sleep. This is the specific subtype of overall sleep that is reduced in depression, even when the individual sleeps too much. Several studies have investigated the question, but a very recent one best illustrates the possible relationship between sleep and insulin/glucose control. The study took "normal" non-diabetic subjects, and selectively reduced their slow wave sleep-- the deep sleep that is often found in naps-- but left the light sleep and the REM sleep (the dreaming sleep that runs usually about 90 minutes per cycle in most people) and studied the effects on insulin release and insulin sensitivity.

Insulin sensitivity is how strongly a given amount of insulin will affect (i.e. lower) blood sugar. High sensitivity means that a given amount can reduce the glucose a lot; low sensitivity means that even in the presence of a lot of insulin, glucose doesn't go down (much.)

Type II diabetes is characterized not by insufficient insulin, but by insulin resistance. By way of analogy, your body is so used to having a lot of glucose in it that it doesn't respond to insulin as well as it did. The study found that thein the past; this is why it becomes more common in overweight and/or older individuals. Selective decrease in SWS-- even when total sleep time was the same--caused marked decreases in insulin sensitivity.

But there's a little more to it. Importantly, people who started with low amounts of SWS had the worst outcome when (what little they had) SWS was decreased.

This is what becomes relevant to people with depression. Depression, in general, reduces SWS even when total sleep time is intact. Obviously, it reduces it even more if overall sleep is reduced as well-- but even patients with hypersomnia ("atypical depression") have decreased SWS. We already know from unrelated studies that patients with depression have higher rates of diabetes-- and this may be one of the causes.

Next up are the medications, which, as a class, have little effect on totalsleep (may reduce it), reduce REM sleep, but increase SWS. This is particularly important for two reasons: first, it may have the potential to mitigate the effect of clinical depression on SWS and diabetes; second, a significant number of people on antidepressants also take sleeping pills-- pills, which, like antidepressants, typically suppress REM sleep but increase SWS and total sleep.

This is clearly not to say that sleeping pills will prevent diabetes; but it does suggest that sleep normalization in the context of the treatment of depression has an effect on the long term morbidity of depression--e.g. Diabetes.

Antipsychotics and Diabetes

May 10, 2006

Glucose Transport

Glucose is absorbed through the small intestine into the blood.

All glucose is taken into cells via hexose transporters: this is facilitated diffusion (no ATP). Facilitated diffusion is passive diffusion through a channel made by a transmembrane protein; the proteins are able to open and close this channel. There are many ways channels can be opened/closed: ligand gated (i.e. neurotransmitter receptors), voltage gated (neurons), or, in the case of hydrophilic molecules such as glucose, mechanically gated: the channel is shaped like a closed "V". Glucose goes to the bottom of the V, causes a conformational change and the "V" opens, but closes at the top (makes an upside down "V".) Glucose can pass, and the V recloses. All diffusion is down a concentration gradient.

The hexose transporters are called, randomly, "Glucose transporters 1-5" (GLUT1-5).

GLUT4 is the main transporter in muscle, fat, and the heart. GLUT4 is insulin-sensitive (though it can also be activated by muscle contraction-- go figure.) In the absence of insulin, GLUT4s are stored in cytomplasmic vesicles floating around in the cytosol. If insulin binds to the insulin receptor (an ATP dependent tyrosine kinase receptor-- NOT the GLUT4), a signal cascade is activated that causes the cytpolasmic vesicle to go to and bind to the plasma membrane and lodge the GLUT4 there. The GLUT4 then allows glucose to diffuse through. When insulin disappears, the insulin receptor reconforms, the signal cascade stops, and the GLUT4 pinches off (by clathrin and other contracting proteins in the cell membrane) into a vesicle again (pinocytosis).

Thus, if there is no insulin: even if there is much glucose, there is no signal for the vesicle to go to the plasma membrane and lodge the GLUT4, so there will be no transport of glucose into the cell; so glucose stays high in the blood. Thus we have Type 1 diabetes.

Insulin also stimulates the creation of glycogen in the liver and muscle. [Insulin activates hexokinase (1st enzyme in glycolysis) as well as phosphofructokinase and glycogen synthase) and inhibits glucose-6-phosphatase ((opposite direction of hexokinase, same reaction) gluconeogenesis).]

Insulin promotes fatty acid synthesis.
Once glycogen synthesis has maxed out (i.e. about 30g, about 20% of the carbohydrate part of a studied meal, max in 4-6hrs,) then fatty acid synthesis IN THE LIVER takes over. Glucose is converted to free fatty acids (FFAs) and dumped back into the blood as lipoproteins-- which are then broken up into FFAs.

FFAs go into the adipose cells of the body. Glucose also goes into adipose cells-- via GLUT-- and are converted into glycerols. Glycerol+FFAs= triglycerides.

Thus, insulin's role is to store fat and/or oxidize glucose. Too little insulin will also trigger protein catabolism.

GLUT1 and GLUT3 account for 95% of the glucose transport to the brain. GLUT1 is for the blood brain barrier (the tight junctuions of the BBB are what require these channels), and GLUT3 is in the neurons. (pic here) GLUT1 is also found in muscle.

These are not insulin dependent (like GLUT4 is) so the brain can continue to get its energy. Not only does the distribution of GLUT 1 and 3 mirror capillary density and areas of relative glucose utilization, the GLUT1/3 densities can change depending on chronically increased (or decreased) need for glucose. Interestingly, nicotine, which increases brain glucose utilization, increases GLUT1/3 but not capillary density.

GLUT2 and 7 are in the liver. GLUT2 can also carry D-fructose.

GLUT5 is in the intestine, and some glial cells of the brain.

Type II diabetes is insulin resistance, not lack of insulin. There is not, at least initially, a problem with the pancreas's secretion of insulin in response to high glucose. The problem is at the level of the insulin receptor and/or GLUT, which become insensitive to the effects of insulin-- because there has been so much of it for so long. (For more info, see: News Physiol Sci. 2001 Apr;16:71-6.

Antipsychotics and Diabetes

The Last Psychiatrist
May 10, 2006

Atypicals and Diabetes: Glucose Transport

Glucose is absorbed through the small intestine into the blood.

All glucose is taken into cells via hexose transporters: this is facilitated diffusion (no ATP). Facilitated diffusion is passive diffusion through a channel made by a transmembrane protein; the proteins are able to open and close this channel. There are many ways channels can be opened/closed: ligand gated (i.e. neurotransmitter receptors), voltage gated (neurons), or, in the case of hydrophilic molecules such as glucose, mechanically gated: the channel is shaped like a closed "V". Glucose goes to the bottom of the V, causes a conformational change and the "V" opens, but closes at the top (makes an upside down "V".) Glucose can pass, and the V recloses. All diffusion is down a concentration gradient.

The hexose transporters are called, randomly, "Glucose transporters 1-5" (GLUT1-5).

GLUT4 is the main transporter in muscle, fat, and the heart. GLUT4 is insulin-sensitive (though it can also be activated by muscle contraction-- go figure.) In the absence of insulin, GLUT4s are stored in cytomplasmic vesicles floating around in the cytosol. If insulin binds to the insulin receptor (an ATP dependent tyrosine kinase receptor-- NOT the GLUT4), a signal cascade is activated that causes the cytpolasmic vesicle to go to and bind to the plasma membrane and lodge the GLUT4 there. The GLUT4 then allows glucose to diffuse through. When insulin disappears, the insulin receptor reconforms, the signal cascade stops, and the GLUT4 pinches off (by clathrin and other contracting proteins in the cell membrane) into a vesicle again (pinocytosis).

Thus, if there is no insulin: even if there is much glucose, there is no signal for the vesicle to go to the plasma membrane and lodge the GLUT4, so there will be no transport of glucose into the cell; so glucose stays high in the blood. Thus we have Type 1 diabetes.


Insulin also stimulates the creation of glycogen in the liver and muscle. [Insulin activates hexokinase (1st enzyme in glycolysis) as well as phosphofructokinase and glycogen synthase) and inhibits glucose-6-phosphatase ((opposite direction of hexokinase, same reaction) gluconeogenesis).]

Insulin promotes fatty acid synthesis.
Once glycogen synthesis has maxed out (i.e. about 30g, about 20% of the carbohydrate part of a studied meal, max in 4-6hrs,) then fatty acid synthesis IN THE LIVER takes over. Glucose is converted to free fatty acids (FFAs) and dumped back into the blood as lipoproteins-- which are then broken up into FFAs.

FFAs go into the adipose cells of the body. Glucose also goes into adipose cells-- via GLUT-- and are converted into glycerols. Glycerol+FFAs= triglycerides.

Thus, insulin's role is to store fat and/or oxidize glucose. Too little insulin will also trigger protein catabolism.

GLUT1 and GLUT3 account for 95% of the glucose transport to the brain. GLUT1 is for the blood brain barrier (the tight junctuions of the BBB are what require these channels), and GLUT3 is in the neurons. (pic here) GLUT1 is also found in muscle.

These are not insulin dependent (like GLUT4 is) so the brain can continue to get its energy. Not only does the distribution of GLUT 1 and 3 mirror capillary density and areas of relative glucose utilization, the GLUT1/3 densities can change depending on chronically increased (or decreased) need for glucose. Interestingly, nicotine, which increases brain glucose utilization, increases GLUT1/3 but not capillary density.


GLUT2 and 7 are in the liver. GLUT2 can also carry D-fructose.

GLUT5 is in the intestine, and some glial cells of the brain.

Type II diabetes is insulin resistance, not lack of insulin. There is not, at least initially, a problem with the pancreas's secretion of insulin in response to high glucose. The problem is at the level of the insulin receptor and/or GLUT, which become insensitive to the effects of insulin-- because there has been so much of it for so long. (For more info, see: News Physiol Sci. 2001 Apr;16:71-6.

Next up: how do antipsychotics affect glucose/insulin/transporters?

From The Last Psychiatrist - May 10, 2006

How Do Antipsychotics Cause Weight Gain?

In order for this post-- and any discussion on antipsychotic induced weight gain-- to make sense, you have to understand one thing: each antipsychotic seems to cause weight gain by a different mechanism, not varying degrees of the same mechanism. Because let me tell you right off the bat: researchers here are far from agreed.

A review of some articles:

In rat pancreatic beta cells, neither clozapine nor haloperidol had any effect on basal insulin release. In the presence of high glucose, haloperidol had no effect on the normal insulin surge, but clozapine inhibited this effect by 40%. How it did this is not clear, as clozapine, in the presence of glucose, completely suppressed electrical activity by hyperpolarizing the membrane potential (i.e. increased K+ conductance.) Haloperidol depolarized (inhibited K+ conductance). Thus, by completely suppressing electrical activity, it should have completely suppressed insulin release-- but it only inhibited 40%. Similarly, haloperidol should have increased insulin release (via depolarization) but it didn't have any effect. We don't know what would have happened if the study had been continued for a year; but note here that the effect on insulin is dependent on the presence or absence of glucose, not the other way around.

Most studies focus on the changes in serum parameters (triglyceride, cholesterol, insulin, etc) and not the mechanism for these changes.

For example, in 112 schizophrenics on meds for 8 weeks, olanzapine, clozapine, risperidone, sulpiride all increased insulin and C reactive peptide, as well as insulin resistance; but only clozapine and olanzapine increased triglycerides and cholesterol, and had a greater impact on insulin, insulin resistance, and C-peptide. What you can't tell is when this happened and what came first: did the insulin go up as a direct effect of the med, and consequently so did cholesterol, or did insulin resistance happen first, etc?

In the first study looking at the drugs' effects on GLUT1-5 mRNA, it was found that mirtazapine increases GLUT4 (muscle/fat) and 5(intestine) mRNA, and haloperidol and olanzapine increase GLUT5. No effect on GLUT1-3. (Contrast with clozapine and risperidone, below.)

The authors propose something interesting about mirtazapine: "Therefore, the increasing effects of mirtazapine on GLUT4 mRNA levels in our study might lead to a decrease in blood glucose levels and to an increase in cellular fat deposition, leading to intermittent or continuous lowering of blood glucose levels with a subsequent increased uptake of carbohydrates and other types of nutrients." In other words, better glucose uptake into cells means more fat inside cells, and less glucose outside cells (hypoglycemia)-- which is a stimulus to eat more.

This is important, so I'll repeat it: the hyperglycemia seen with olanzapine and haloperidol is here proposed to be due to the acute lowering of blood glucose (because of increased transport), and thus an increase in eating and fat deposition, and consequently insulin resistance and hyperglycemia; not a direct affect on glucose metabolism.

(Consistent with olanzapine's effect on GLUT5 (and not on carbohydrate metabolism, per se), metformin did not prevent weight gain in 40 people on 10mg olanzapine (all gained 5-6kg in 14 weeks.)

In (male C57) mice, over a 6 month period, clozapine, chlorpromazine and quetiapine induced hyperglycemia via effects on glucose transport. haloperidol and amisulpiride have little effect on GLUT, and were found not to induce hyperglycemia. Risperidone had a medium effect on hyperglycemia, but at the lower doses.

Using rat pheochromocytoma cells, clozapine and risperidone both inhibited glucose transport (i.e. GLUT3).

Desmethylclozapine (a metabolite) was an even more potent inhibitor, while clozapine-N-oxide, the other metabolite, had no effect on glucose transport. Clozapine and fluphenazine also inhibited glucose transport in (rat) muscle cells. The drugs block glucose transport in a non-competitive (i.e. allosteric) manner (and tricyclics appear to work in the same way.) What is interesting about this is that different people metabolize clozapine differently, and perhaps those who create more desmethylclozapine get more hyperglycemia than those who make less (and/or more clozapine-N-oxide.

A follow-up study tried to correlate the toxicity of these drugs to cells to their inhibition of glucose transport.

They found that clozapine, desmethylclozapine, quetiapine and fluphenazine were toxic to cells; risperidone was minimally toxic; and olanzapine actually promoted cell growth.

Quetiapine, olanzapine and clozapine all inhibited glucose transport about the same amount, and in a dose dependent manner. (Remember: haloperidol and sulpiride don't.)

However, if the cells were exposed to drug for a longer time, fluphenazine greatly inhibited glucose uptake, clozapine had no effect, and olanzapine increased glucose uptake. In other words, the toxic typicals only need a sort exposure to kill a cell, while less toxic atypicals need prolonged exposure. Also, fluphenazine increased GLUT3, and the atypicals had little or no effect (as found above.)

Olanzapine was found not to affect either the basal or the insulin stimulated glucose transport via GLUT1 or 4. (Fun fact: bovine serum albumin (or impurities therein), used to replicate the fact that olanzapine is highly (93%) protein bound, actually increased basal glucose transport, making suspicious all studies previosuly done with BSA.) This contradicts the findins of the Dwyer articles, above, where antipsychotics had inhibitory effects on glucose transport. A possible explanation could be dosing: this study used doses comparable to 20mg, while others used 20x that amount.

Another study, in humans, found that neither olanzapine nor risperidone affected acute (3 week) insulin sensitivity. Again, what happens after you get heavy is up for debate.

So what we have here is confusion, but:

1. acute, high dose in vitro studies indicate that typicals>atypicals inhibit glucose transport, but haloperidol does not.

1b. Typicals are toxic to cells, atypicals less so, and olanzapine promotes cell proliferation.

2. Normal dose and human studies show no effect on insulin dependent glucose transport (i.e. GLUT4) but there are effects on small intestine absorption (GLUT5) with olanzapine and haloperidol.

3. Clozapine inhibits insulin release in the presence of glucose, but haloperidol doesn't.

4. Acute effects may be different than chronic. i.e. even though antipsychotics may not directly affect insluin resistance or glucose transport, if they make you hungry or increase fat over time, this could result in later insulin resistance, hyperglycemia, etc.

Weight Gain & Olanzapine

From The Last Psychiatrist - May 14, 2006

Olanzapine's Weight Gain: Does What You Eat Matter More Than How Much?

The authors of this article have an interesting hypothesis, upon which I speculate wildly. But it is fascinating:

GLUT5, is found primarily in the small intestine (though also in muscle and kidneys.) What's interesting about it is that it transports fructose, which in turn directly stimulates additional GLUT5 mRNA expression. You eat fructose, this increases the expression of GLUT5 in the intestinal villi, which increases the transport of fructose. So the more fructose you eat, the more readily you can absorb it.

Now fructose doesn't stimulate insulin secretion. Since insulin regulates leptin, fructose actually reduces leptin. Fructose increases ghrelin. So you get hungry. Fructose goes to the liver and is metabilized to acyl glycerols, and consequently result in increased triglycerides.

So you have a situation in which Remeron and olanzapine (and high dose Haldol) cause an increase in GLUT5 expression; if they are also eating fructose (read: high fructose corn syrup) this is causing an additional expression in GLUT5, and hunger, and increased triglycerides... if one wants to conduct a useful experiment, find out if the people who gain the most weight on olanzapine are those who consume the most high fructose corn syrup (and not just those who eat the most.) In other words, can you gain weight on olanzapine if you are eating Atkins?

(NB: there are many who want to believe that olanzapine causes weight gain by increasing leptin; and so fructose and GLUT5 lowering leptin seems confusing. olanzapine, as shown above, actually decreases leptin, acutely. (And clozaril has either no effect, or minimal lowering.) Letpin only increases with increased fat-- i.e. as a consequence of fat, not as the cause of fat. Those who have found increases in serum leptin do so only after chronic administration, and resultant weight gain (for example, in a study of 13 schizophrenics on olanzapine who showed a small increase in leptin after 4 weeks-- and after a 2 kg weight gain; or 6 week animal study finding increased fat and leptin. The question, as noted by the authors, is whether the acute hypoleptinemia and hypoglycemia is what triggers hunger and an ultimate increase in fat, leptin, glucose and insulin. )