Re: Dangerous sulfonylureas (was: New to the List)

[Guest guest]

> anne, glyburude/micronase/diabeta all the same thing, it's surely

> there. Sam

Nope, no luck. Closest I got was Diabinese whose chemical name is

Chlorpropamide which is also a sulphonylureas

anne

[Guest guest]

In a message dated 10/17/2000 8:50:57 PM Eastern Daylight Time,

ottercritter@... writes:

<< glucophage (Metformin >>

this is not always the way to go, as far as dm meds go, most have a hard time

with the gastro/intestinal side effects, plus must be stopped if you are ill

or have an infection as it has shown to cause other problems which could be

worse, make sure your dr and pharmacist give you all the facts on this med if

you choose it, as in times of illness you still need to care for your dm

which means possibly sliding scale insulin of regular insulin for just the

times of illness.

Just a suggestion

carol

[Guest guest]

anne King wrote:

<< Oh fabulous! Thank you for the heads up! Why don't doctors warn you

about this?? >>

A knowledgeable diabetic once said, " When doctors prescribe this

old-fashioned, wrong-headed drug, years after newer, safer medications have

been on the market, it's an admission that they haven't cracked a medical

book in years. "

<< I recall that the diabetes educator mentioned something about the

medication only working for about 5 years and then I'd have to go onto

insulin injections. When I asked her why, she said " That's just the way it

is, they (meaning the medical profession I presume) don't know why. " >>

We certainly do know why. There were some earlier tests showing that

sulfonylureas injected beneath the skin of mice caused cell death. The

mechanism by which sulfs operate is also widely-known ... they overdrive

already-worn-out pancreas beta cells until complete exhaustion. And then -

voila - you are needlessly converted to a type 1 - by the wrong meds. The

nature of type 2 is that our modern diet and a sedentary lifestyle create

insulin resistance, which worsens until we become diabetic. When we are

diagnosed (often years after the disease manifested itself), what our bodies

desperately need is for our worn-out beta cells to get a rest, so they can

recover. We help this along by limiting our carbohydrate intake (i.e., the

vast majority of type 2's whose pancreases are in pretty bad shape), by

exercising regularly to " burn up the carbs " , and by weight loss. I don't

know how much your doctor and diabetes educator will appreciate my

criticism, but my goal in life is to save the lives of my fellow diabetics.

There are online diabetics who know more about this disease than doctors and

educators. They " live the life " every day, they do years of research, and

they use their own bodies as guinea pigs. We call it " my body; my science

experiment. " I don't blame your educator and your doctor if they don't want

to take the word of " some stranger on the internet. " So here's a study to

show both of them ...

<< I'm going to print this out and show my doctor and insist that they

change my meds immediately. I can't afford to have a hypo at all. I have

developmentally disabled children who wouldn't know what to do if I had one!

>>

Ask for the Aussie equivalent of glucophage (Metformin). And have your liver

function checked to make sure you're okay on it. There are several other

good diabetes out there too, but glucophage is an old-timer ... been tested

on a *lot* of diabetics. We'll be happy to suggest other meds to your doctor

if for some reason you can't take that one. One beauty of glucophage is it

tends to cause gradual weight loss - which helps the insulin resistance.

<< I was also wondering if anyone had a good link for a diabetic food

regimen. I suspect that the info that the Educator is also way off. The

diet recommended consists of high carbs and low fats. >>

Ahem - forget anything nice I said about the educator. I got into it with my

dietitians when I was diagnosed. I kept saying, " But carbohydrates - all

carbohydrates - are the problem for us diabetics. How can I get better if

you want me to eat MORE of them? They don't understand that diabetes is the

800-pound gorilla. Job No. 1 for us is doing whatever it takes to normalize

our glucose readings. If we don't diabetes can kill us. And no amount of

low-fat food is going to " fix " dangerously-high triglycerides and

miserably-low HDL and hypertension ... all problems for the majority of

diabetics who aren't informed about the importance of appropriate diet.

Susie in sunny Arizona

*************

Many of you know J. C. (Jim) Hartmann, who has offered many valuable

insights to our group, to LC-DIABETES, and to the newsgroup

misc.health.diabetes. He revealed in private e-mail that he had found a

study pertaining to beta cell " burnout " caused by taking sulfonylureas. Here

is a copy of his recent post to misc.health.diabetes ...

Susie

Someone on another list pointed out the following new research, which seems

to verify the long-held, but never previously verified, association between

the sulfonylurea drugs and beta cell " burnout. "

In a private e-mail, one of our list members suggested that I post this

information, along with a thumbnail description for those who do not wish to

wade through the med-speak or subscribe to Medscape. So here

goes...

Sulfs (glucotrol, glipizide, glyburide, et al.) cause the pancreas to

produce additional insulin. It also causes the beta cells to produce

additional amylin. This study seems to show that the hyperamylinemia has

deleterious effects to the beta cells themselves, as well as blood vessel

walls, glomerulus in the kidneys, and nerves, etc., and seems to explain why

hyperinsulinemia/hyperamylinemia is the cause of so many of the 'opathies

found in T-2 DM, not to mention beta-cell failure.

Despite the silly term of " remodeling the pancreas " , those on sulfs may want

to reconsider their continued use, and substitute Metformin (glucophage) or

one of the 'glitizones, or exogenous insulin injections. Low-carb

doctrine gets a boost from this, too.

The link is at:

http://diabetes.medscape.com/SMA/SMJ/2000/v93.n01/smj9301.03.hayd/smj9301.03

..hayd-01.html

Well, that URL Jim Hartmann was kind enough to provide (along with his

concise analysis) is tricky to pull up. Also, the research paper is strung

out over several pages. For those of you who have created a folder for

scientific research (I hope that includes every one of you), here's the full

study, in unformatted form. (What I do is just create extra folders in my

Outlook Express Inbox, with titles like " Diabetes, " " Low-carb Yummies, "

etc.)

I am providing this because I fought some bloody battles in the newsgroup

misc.health.diabetes over this. Researchers have been dancing around this

issue for years. They referred to it merely as " secondary failure, " and

claimed no one knew the cause. So for years, diabetics have been taking a

medicine, in the belief that their doctor was helping them, and it has been

shortening the life of their pancreas, causing other serious health

problems, and shortening their lives. I hope you will spread the word.

Susie

The URL, once again, is

http://diabetes.medscape.com/SMA/SMJ/2000/v93.n01/smj9301.03.hayd/smj9301.03

..hayd-01.html

From: " Southern Medical Journal " -- Remodeling of the Endocrine Pancreas:

The Central Role of Amylin and Insulin Resistance

M. R. Hayden, MD, Camdenton, Mo, Suresh C. Tyagi, PhD, Department of

Cardiovascular Atherosclerosis, Metabolism and Aging, Camdenton Medical

Center, Camdenton, Mo.

Abstract:

Background. Remodeling of the endocrine pancreas, caused by the deleterious

effects of amylin as it is co-synthesized, co-packaged, and co-secreted with

insulin, gives clinicians and researchers cause to ponder.

Methods. A literature search was done, and relevant publications and texts

on amylin and islet amyloid polypeptide (IAPP) were reviewed.

Results:

The mechanisms and clinical consequences attributed to the remodeling of the

endocrine pancreas, along with proposals for reevaluating the methods of

treating patients who have type 2 diabetes are illustrated and discussed.

Conclusions:

In addition to controlling the devastating effects of glucotoxicity,

lipotoxicity, and hypertension, we should consider the newer hypoglycemic

agents with regard to their effects on the remodeling of the endocrine

pancreas. This remodeling results in structural and subsequent functional

changes, causing continued elevations of hemoglobin A1C. Studies are

indicated to determine whether amylin (IAPP) may be implicated in the

remodeling of the arterial vessel wall, the glomerulus of the kidney, and

the cardiac interstitium. [south Med J 93(1): 24-28, 2000. © 2000 Southern

Medical Association]

Introduction:

Type 2 diabetes mellitus affects about 15 million people in the United

States. An additional 15 million are believed to have undiagnosed

diabetes.[1] Approximately 10% of people aged 65 and older are affected, and

80% of the type 2 diabetics are overweight.

As we approach the new millennium, a large sector of the US population (the

" baby boom generation " will become the " senior boom generation " ) that has

controlled the economy, that will play a large part in the future of health

care and its delivery, and that will likely increase these numbers of type 2

diabetics exponentially. Also, as the Third World countries increase their

social economic status, we can expect an exponential rise in the numbers of

type 2 diabetics globally. With type 2 diabetes increasing throughout the

world, we may wish to review our treatment modalities as they relate to

remodeling of the endocrine pancreas.

The Endocrine Pancreas:

We are concerned here with the endocrine portion of the pancreas, consisting

of the pancreatic islets (islets of Langerhans). It is estimated that there

are 1 million islets per pancreas, weighing between 1.0 and 1.5 g, or

1/100th of the total weight of the pancreas. The islets contain many

capillaries.[2] The three primary cell types within the pancreatic islets

are (1) beta cells (60%), which produce and secrete insulin, as well as

amylin, C peptide, proinsulin, and preproinsulin; (2) a cells (25%), which

synthesize glucagon; (3) d cells (10%), which synthesize somatostatin; and

(4) other cells (5%) pancreatic polypeptide, D1, and enterochromaffin.

Because the islet is so vascular, the beta cell is sensitive to the glucose

concentration and increases insulin synthesis as the plasma glucose level

becomes elevated. Insulin synthesis begins as a preprohormone, a single 109

amino acid preproinsulin. Processing of the preproinsulin by the removal of

a 23 amino acid leader sequence produces proinsulin, which is folded and

crosslinked by disulfide bonds to an 86 amino acid. Endopeptidases within

the secretory granules then convert proinsulin to equimolar amounts of C

peptide (31 amino acid) and insulin (51 amino acid). As the beta cell is

synthesizing insulin, it is synthesizing the 37 amino acid amylin (Figs 1

and 2).

The Remodeling Process:

Amylin ...

Amyloid deposition was first described in 1901 by Opie[3] and by

Weichselbaum and Stangl.[4] They referred to this Congo red-staining

material found within the islet as islet amyloidosis or hyaloidosis of the

islets. They noted that these deposits were predominantly found in patients

with diabetes.

Amylin was described in 1987 by two independent groups of

investigators,[5,6] who discovered this 37 amino acid polypeptide while

working with AE amyloid in patients with type 2 diabetes. Amylin is

co-synthesized, co-packaged, and co-secreted with insulin by the beta cells'

secretory granule. It may be referred to as insulin's " fraternal twin. " In

type 2 diabetes, amylin values are elevated, as are insulin values.[7,8] The

37 amino acid structure of amylin is depicted in Figure 3. The elevated

levels of amylin result in the continued laying down of the IAPP deposits

within the perivascular regions and interstitium of the islet (Figs 4, 5,

and 6).

In addition to remodeling, fibrils made from IAPP have been reported to have

a toxic effect on monolayers of beta cells in vitro. Although this toxic

effect of islet amyloid has yet to be proven in vivo, there is a progressive

loss of beta cells as the islet continues the remodeling process. As the

remodeling continues, the secretory response of the beta cell progressively

decreases, with the potential for eventual failure.[9,10] Advanced

glycosylation end products have recently been shown to accelerate the

deposition of the IAPP fibrils associated with amyloid formation.[11] These

findings may help to explain why deposition of the islet amyloid, referred

to as AE amyloid, is more severe the longer the patient has had type 2

diabetes.

Beta Cells and Insulin Resistance:

Insulin resistance may be defined as the resistance of peripheral cells

(skeletal muscle and adipocyte) to insulin-mediated glucose uptake, which

results in elevations of blood glucose.[12] The pancreatic beta cell then

synthesizes more insulin and amylin, resulting in hyperinsulinemia and

hyperamylinemia. Glucose toxicity only compounds this vicious cycle.

Hyperamylinemia:

Elevated levels of amylin may induce apoptosis of the beta cell and cause a

self-aggregation and polymerization to the extracellular matrix within the

islet, forming islet AE amyloid in contrast to AA amyloid seen in chronic

inflammatory diseases, AL amyloid seen in multiple myeloma, and b amyloid

seen in Alzheimer's disease (Figs 4, 5, and 6).

The metabolic syndrome of insulin resistance might be present for 5 to 7

years before the clinical presentation of hyperglycemia. During this time,

the remodeling of the endocrine pancreas will be evolving to form the

changes seen in Figures 4, 5, and 6. Therefore, we may wish to rethink our

current methods of treating type 2 diabetes. We must ask whether we should

allow this hyperinsulinemia/hyperamylinemia state to continue or even

complicate matters by using insulin secretagogues, thus increasing

endogenous insulin and amylin. Currently, we are at a cross-roads in making

this decision.

New Oral Hypoglycemic Agents:

Fortunately, we have at our disposal five new individually unique

medications to arrest the ongoing remodeling within the pancreas while

controlling the glucose toxicity associated with type 2 diabetes. We have

had metformin since 1995 in the United States. Its primary action is in

preventing gluconeogenesis in the liver, and its secondary action is in

alleviating the insulin resistance peripherally.[13] We have had the first

thiazolidinedione (troglitazone) since 1997 in the US. Its primary action is

that of peripherally improving insulin resistance, and its secondary action

prevents gluconeogenesis at higher doses.[13] The second and third

thiazolidinediones, which will be released this year (1999), are

rosiglitazone and pioglitazone, a peroxisome proliferator-activated receptor

gamma agonist similar to troglitazone.[15] Repaglinide (the first of a new

class of insulin secretagogues, the meglitinides) has been approved in the

United States since 1998. Its primary action is on the potassium ATPase

sensitive receptor of the beta cell at a site different from that targeted

by the sulfonylureas. It is chemically a benzoic acid derivative that is

structurally different from the sulfonylureas and that has a rapid onset and

short duration of action, elevating insulin only in the immediate

postprandial period.[16]

In addition to weight loss, exercise, and dietary changes, it is time to

consider the beneficial effects of monotherapy with metformin or the

thiazolidinediones (troglitazone, rosiglitazone, or pioglitazone) as

monotherapy or in combination if either should fail alone to reduce

glucotoxicity. Then, the insulin secretagogue repaglinide (with its short

duration of action) or exogenous insulin can be added if necessary to gain

glucose control.

The ultimate goal in treating type 2 diabetes is to control the

glucotoxicity without elevating the endogenous insulin and subsequent amylin

levels. By using this approach, we may be able to control the deleterious

effects of remodeling of the endocrine pancreas. In type 2 diabetes, it is

vital to control the devastating effects of glucotoxicity, lipotoxicity (the

toxicity induced by dyslipidemia), and hypertension.

Remodeling of the Arterial Vessel Wall:

In addition to the remodeling of the endocrine pancreas in type 2 diabetes,

there is also extensive remodeling of the arterial vessel wall with

accelerated atherosclerosis. As an aid in planning prevention and treatment

of this devastating macrovascular complication, the following acronym was

created:

R -- Reductase inhibitors (HMG-CoA), which decrease modified low-density

lipoprotein (LDL) cholesterol (ie, oxidized, acetylated LDL cholesterol) and

lessen endothelial cell dysfunction, thus decreasing the oxidative stress to

the arterial vessel wall.

A -- ACEi-prils and ARBS-sartans, which inhibit the effect of angiotensin II

locally as well as systemically. They affect the hemodynamic stress through

their antihypertensive effect, as well as the deleterious effects of

angiotensin II on cells at the local level (injurious stimuli). They also

lessen endothelial cell dysfunction.

A -- Aggressive control of diabetes by decreasing modified glycated LDL

cholesterol and decreasing endothelial cell dysfunction, glucose toxicity,

and reductive stress to the intima.

S -- Statins, which improve plaque stability independent of cholesterol

lowering, decrease endothelial cell dysfunction, and prevent angiogenesis

associated with the arterial vascular remodeling that destabilizes the

unstable atherosclerotic plaque.[17]

Receptor-Mediated Disease:

In the insulin-resistant patient, the destructive aspects of hypertension

often aggravate the underlying glucotoxicity associated with type 2

diabetes. It is engaging to now be able to show a mechanism that ties

insulin and amylin to hypertension through a receptor-mediated response.

The insulin receptor is a G-protein-coupled transmembrane receptor, as is

the AT-1 receptor. Nickenig and colleagues[18] recently showed that insulin

causes an upregulation of the AT-1 receptor. This was associated with an

increased functional response by the vascular smooth muscle cell.

Angiotensin II caused a much more significant release of intracellular

calcium when cells were cultured with 100 nmol/L of insulin for 24 hours.

Velloso and Folli[19] showed that there was " cross-talk " between the insulin

and angiotensin signaling systems. Elevated insulin levels cause a

continuous bombardment of the insulin receptors. The continued

autophosphorylation of the tyrosine kinases of the insulin receptor may

create a biochemical electrical discharge to activate the

autophosphorylation of the AT-1 receptor, thus causing the activation of the

AT-1 receptor independent of angiotensin II.

and McNally[20] found that there were amylin binding sites in the

kidney and that amylin infusion in nine healthy men created a steady state

of subnanomolar amylin levels. This led to significant increases in plasma

renin and aldosterone concentrations. The interactions of insulin and amylin

through the G-protein-coupled transmembrane receptors may play an important

role in the association of not only insulin resistance and hypertension, but

also the associated cardiovascular disease.

Discussion:

The terms beta-cell fatigue, beta-cell failure, and beta-cell burnout are

frequently used to describe the progressive nature of type 2 diabetes (ie,

the progressive elevations of HbA1C). As noted, the remodeling of the

endocrine pancreas caused by IAPP results in structural and subsequent

functional changes associated with this phenomenon. It is believed that the

" islet fibrosis " AE amyloid induced by amylin (IAPP) plays the central role

in the development of the beta-cell failure associated with type 2 diabetes.

A change in our current methods of treating type 2 diabetes should be

entertained, since we now have available newer medications that decrease

glucotoxicity without elevating endogenous insulin/amylin levels.

Any treatment that would slow or halt the remodeling process may aid in the

preservation of beta-cell function and its secretory defect. Since our

submission of this article in January 1999, Kahn and Verchere[21] have

published the results of their landmark study in which they were able to

show that apolipoprotein E and perlecan (a heparin sulfate proteoglycan)[22]

were present in islet amyloid in addition to amylin. In their human IAPP

transgenic mouse model, they showed that islet amyloid deposition is an

early feature and that further deposition is related to beta-cell mass

reduction. In addition, they showed increased dietary fat-induced islet

amyloid formation. With regard to future directions, studies should be done

to see if amylin may be implicated in the remodeling of the arterial vessel

wall, the glomerulus and tubules of the kidney, the interstitium of the

perineuronal tissue, and the interstitium of the heart. If so, this could

explain why many patients have multiple opathies at the time of the initial

diagnosis of type 2 diabetes mellitus.

[Guest guest]

anne, I'll check for you, Sam

Yeah, I think thats an old one that requires high doses.

[Guest guest]

anne

check this

http://www1.mosby.com/genrxfree/Top_200_1999/Drugs/E1368.htm