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From: Jefferson on 17 Jan 2007 20:18
By the time someone is diagnosed with type 2 DM their beta-cells are not
secreting enough insulin to compensate for their glucose levels. In
animal models, Byetta has succeeded in expanding beta-cell mass. Januvia
has some of the same effects as Byetta. It is my opinion that neither of
these drugs can overcome or restore beta-cell function without beta-cell
rest which allow these cells to store up insulin in their granules.
Insulin injections can give beta-cells some rest. I was able to maintain
fasting blood glucose to an average just above 87 mg/dl for a full year
using the slow acting insulin Ultralente at bedtime, but I didn't have
that kind of control over postprandial blood glucose levels. The
following are some excerpts that support my opinion:

Overnight inhibition of insulin secretion restores pulsatility and
proinsulin/insulin ratio in type 2 diabetes -
http://intl-ajpendo.physiology.org/cgi/content/full/279/3/E520
"The results of these clinical experiments suggest the conclusion that
.... cellular depletion of immediately secretable insulin that can be
overcome by beta -cell rest."

A scholar.google.com search for "beta cell rest"+"type 2"+diabetes+human
- http://tinyurl.com/2xjm5w

Pulsatile Insulin Secretion Dictates Systemic Insulin Delivery by
Regulating Hepatic Insulin Extraction In Humans -
http://diabetes.diabetesjournals.org/cgi/content/full/54/6/1649
"In conclusion, in humans, ~80% of insulin is extracted during the first
liver passage. The liver rapidly responds to fluctuations in insulin
secretion, preferentially extracting insulin delivered in pulses. The
mass (and therefore amplitude) of insulin pulses traversing the liver is
the predominant determinant of hepatic insulin clearance. Therefore,
through this means, the pulse mass of insulin release dictates both
hepatic (directly) as well as extra-hepatic (indirectly) insulin
delivery. These findings emphasize the dual role of the liver and
pancreas and their relationship mediated through magnitude of insulin
pulse mass in regulating the quantity and pattern of systemic insulin
delivery."

Functional and Molecular Defects of Pancreatic Islets in Human Type 2
Diabete - http://diabetes.diabetesjournals.org/cgi/content/full/54/3/727
"Accordingly, 24-h exposure to glutathione (GSH) significantly improved
glucose-stimulated insulin release and decreased nitrotyrosine
concentration, with partial recovery of insulin mRNA expression. These
results provide direct evidence that the defects of insulin secretion in
type 2 diabetic islets are associated with multiple islet cell
alterations. Most importantly, the current study shows that the
functional impairment of type 2 diabetic islets can be, at least in
part, reversible. In this regard, it is suggested that reducing islet
cell oxidative stress is a potential target of human type 2 diabetes
therapy. Many studies suggest that type 2 diabetic patients are
subjected to chronic oxidative stress Hyperglycemia and increased free
fatty acid concentration can contribute to the formation of reactive
oxygen species, which in turn damage cell proteins and DNA. In islet
�-cells, oxidative stress is even more dangerous than in other tissues
because of the low intrinsic antioxidant capacity of the �-cell. In our
experiments, we found that levels of nitrotyrosine and 8-OHdG, which are
markers of oxidative stress, are higher in type 2 diabetes than in
control islets, and for the first time we demonstrate a correlation
between the concentration of these compounds and the degree of insulin
secretion impairment. Notably, the addition of GSH in the incubation
medium determined reduction of oxidative stress (as suggested by the
diminished levels of nitrotyrosine), improved glucose-stimulated insulin
secretion, and increased insulin mRNA expression. ... Activation of AMPK
is considered to have beneficial effects on diabetes because it improves
insulin action in the muscle and liver. This kinase has been recently
implicated in the control of insulin secretion." Note that glutathione
is a natural, endogenous antioxidant. Also metformin is know to activate
AMPK and is therefore one of it's positive benefits.

Frank
__________
The following are repeats that I am trying to place in the same link on
Google group archives.

Incretin-Based Therapies -
http://www.medscape.com/viewprogram/5720_pnt

# Exenatide
Anne L. Peters, MD, FACP

# Incretin Analogs Other Than Exenatide
Laurie L. Baggio, MSc, PhD
Daniel J. Drucker, MD, FRCPC

# DPP-IV Inhibitors
Ravi Retnakaran, MD, MSc, FRCPC
Daniel J. Drucker, MD, FRCPC

Full article for Reference #5 in the "Incretin Analogs Other Than
Exenatide" article above:
Design of a Long-Acting Peptide Functioning as Both a Glucagon-Like
Peptide-1 Receptor Agonist and a Glucagon Receptor Antagonist -
http://www.jbc.org/cgi/reprint/M600127200v1

The role of gut hormones in glucose homeostasis -
http://www.jci.org/cgi/content/full/117/1/24

Differences in Fecal Microbiota in Different European Study Populations
in Relation to Age, Gender, and Country: a Cross-Sectional Study -
http://aem.asm.org/cgi/content/full/72/2/1027

Lactate-Utilizing Bacteria, Isolated from Human Feces, That Produce
Butyrate as a Major Fermentation Product -
http://aem.asm.org/cgi/content/full/70/10/5810

> What have you in mind?

The indirect increase in endogenous GLP-1 production by GLP-2 inducement
of more gut type L-cells. "GLP-2 exerts trophic effects on the small
and large bowel epithelium via stimulation of cell proliferation and
inhibition of apoptosis." http://tinyurl.com/v2ql4

> Not only bacteria but the so called archea which are not bacteria can
> produce Butyrate. They use the metabolic products of bacteria such as
> hydrogen and in turm have a product of Butyrate. This helps the
> bacteria because reducing the products in the environment aids in >
> their numbers as usually products become a limiting factor.

A scholar.google.com search for archea+butyrate+humans resulted in 341
finds - http://tinyurl.com/ykusbq. Adding "trial" to the search terms
above reduces the finds to 40. Can you narrow these list down?

Maximizing the "incretin effect" through diet and supplements #1 is
focused on dietary fatty acids - http://tinyurl.com/72m9e

Maximizing the "incretin effect" through diet and supplements #2 is
focused more on aspects of proglucagon gene expression and related GLP-1
secretion - http://tinyurl.com/bj9vg

Maximizing the "incretin effect" through diet and supplements #3, the
general topic of this subthread is on fiber and the sections of the
intestines - http://tinyurl.com/c79xq

Maximizing the "incretin effect" through diet and supplements #4 : This
aspect of the series relates to proteins, amino acids, and peptones,
particularly to their impact on the incretins produced in the
intestines. http://tinyurl.com/8chhx

There was a poster who went by Calypso that reported anecdotal
improvement in blood glucose. I was trying to establish a scientific
basis in this investigation to rationalize doing a similar approach to
Calypso's. It did improve my lipid panel somewhat using inulin and
yogurt when tested 9 months later, but not greatly since it was already
excellent after 3 or so years of FiberOne, fish oil, whey protein, and
some other things, but blood glucose control did not improve. FBG was
normal at 87 mg/dl at the same point in time as the best lipid panel.
The "Slide 7. Postprandial Glucose Contribution to A1c" gives some
notion of the relative contribution of FBG and Postprandial blood
glucose to A1c - http://www.medscape.com/viewprogram/5552_pnt. So in my
case postprandial blood glucose has been the main contributor to A1c for
over 5 years. A search resulted in about 7,680 finds for
glucose+levels+colon+"type 2" which is not limited enough for isolating
the colon blood glucose level issue. Calypso may have had better
glucose control or a better mix of microflora so those kind of questions
are up in the air. A more formal trial would need to be conducted to
account for variables that I did not initially consider.

Tales from the crypts: regulatory peptides and cytokines in
gastrointestinal homeostasis and disease -
http://jcem.endojournals.org/cgi/content/full/90/8/4888

Regulation of Pancreatic Beta-Cell Mass -
http://physrev.physiology.org/cgi/content/full/85/4/1255
" Neogenesis from progenitor cells inside or outside islets represents a
more potent mechanism leading to robust expansion of the beta-cell mass,
but it may require external stimuli. For therapeutic purposes, advantage
could be taken from the surprising differentiation plasticity of adult
pancreatic cells and possibly also from stem cells. Recent studies have
demonstrated that it is feasible to regenerate and expand the beta-cell
mass by the application of hormones and growth factors like
glucagon-like peptide-1, gastrin, epidermal growth factor, and others.
Treatment with these external stimuli can restore a functional beta-cell
mass in diabetic animals, but further studies are required before it can
be applied to humans." There are current clinical trials being
conducted for both type 1 and type 2 diabetics.

Pancreatic epithelial plasticity mediated by acinar cell
transdifferentiation and generation of nestin-positive intermediates -
http://dev.biologists.org/cgi/content/full/132/16/3767

Regeneration of the pancreatic � cell
http://www.jci.org/cgi/content/full/115/1/5

Relationship Between �-Cell Mass and Fasting Blood Glucose Concentration
in Humans - http://care.diabetesjournals.org/cgi/content/full/29/3/717

Figure 1� Relationship between percentage of pancreas volume occupied by
�-cells and fasting plasma glucose in obese humans without insulin or
oral antidiabetic treatment -
http://care.diabetesjournals.org/cgi/content/full/29/3/717#F1

Islet growth and development in the adult -
http://jme.endocrinology-journals.org/cgi/reprint/24/3/297

�-Cell Deficit and Increased �-Cell Apoptosis in Humans With Type 2
Diabetes -
http://diabetes.diabetesjournals.org/cgi/content/full/52/1/102

Insulin resistance and pancreatic � cell failure -
http://www.jci.org/cgi/content/full/116/7/1756

Dietary fat and insulin action in humans
http://tinyurl.com/pwyhx

The above article has been cited 72 times in later articles.
http://tinyurl.com/gu4l4

Inflammation and insulin resistance
http://www.jci.org/cgi/content/full/116/7/1793
From: Priscilla H. Ballou on 18 Jan 2007 12:55
In article <zKSdnWq7YI7cVjPYnZ2dnUVZ_ompnZ2d(a)adelphia.com>,
Jefferson <xyz(a)adelphia.netng> wrote:

> By the time someone is diagnosed with type 2 DM their beta-cells are not
> secreting enough insulin to compensate for their glucose levels. In
> animal models, Byetta has succeeded in expanding beta-cell mass. Januvia
> has some of the same effects as Byetta. It is my opinion that neither of
> these drugs can overcome or restore beta-cell function without beta-cell
> rest which allow these cells to store up insulin in their granules.
> Insulin injections can give beta-cells some rest.

So can low-carbing.

Priscilla
From: Charly Coughran on 18 Jan 2007 14:03
"Priscilla H. Ballou" <vze23t8n(a)verizon.net> wrote in
news:vze23t8n-9492E2.12552918012007(a)individual.net:

> In article <zKSdnWq7YI7cVjPYnZ2dnUVZ_ompnZ2d(a)adelphia.com>,
> Jefferson <xyz(a)adelphia.netng> wrote:
>
>> By the time someone is diagnosed with type 2 DM their beta-cells are
>> not secreting enough insulin to compensate for their glucose levels.
>> In animal models, Byetta has succeeded in expanding beta-cell mass.
>> Januvia has some of the same effects as Byetta. It is my opinion that
>> neither of these drugs can overcome or restore beta-cell function
>> without beta-cell rest which allow these cells to store up insulin in
>> their granules. Insulin injections can give beta-cells some rest.
>
> So can low-carbing.
>
> Priscilla
>

So can daily exercise, insulin resistance targeting drugs, and carbohydrate
absorption slowing drugs. There are a number of methods to attack the
problem and the most appropriate depends on the particular circumstances.

Also, there is another complicating factor. Hyperglycemia, in and of
itself, is toxic to the beta cells. This is a separate problem from Beta
cell stress and they are difficult to distinguish at a clinical level.

As a side issue, while suggestive, I would be careful not to over estimate
the relevance of findings in animal models.

Charly Coughran
ccoughran(a)DELETE_TO_RESPOND_UCSD.EDU
From: Jefferson on 19 Jan 2007 13:22
Charly Coughran and Priscilla Ballou:
> "Priscilla H. Ballou" <vze23t8n(a)verizon.net> wrote in
> news:vze23t8n-9492E2.12552918012007(a)individual.net:
>
>
>>In article <zKSdnWq7YI7cVjPYnZ2dnUVZ_ompnZ2d(a)adelphia.com>,
>> Jefferson <xyz(a)adelphia.netng> wrote:
>>
>>
>>>By the time someone is diagnosed with type 2 DM their beta-cells are
>>>not secreting enough insulin to compensate for their glucose levels.
>>>In animal models, Byetta has succeeded in expanding beta-cell mass.
>>>Januvia has some of the same effects as Byetta. It is my opinion that
>>>neither of these drugs can overcome or restore beta-cell function
>>>without beta-cell rest which allow these cells to store up insulin in
>>>their granules. Insulin injections can give beta-cells some rest.
>>
>>So can low-carbing.
>>
>>Priscilla
>>
> So can daily exercise, insulin resistance targeting drugs, and carbohydrate
> absorption slowing drugs. There are a number of methods to attack the
> problem and the most appropriate depends on the particular circumstances.
>
> Also, there is another complicating factor. Hyperglycemia, in and of
> itself, is toxic to the beta cells. This is a separate problem from Beta
> cell stress and they are difficult to distinguish at a clinical level.

Why do you see glucotoxicity as not being beta cell stress? It can
result in apoptosis.
>
> As a side issue, while suggestive, I would be careful not to over estimate
> the relevance of findings in animal models.

Agreed! In days/weeks time some mouse models have expanded beta-cell
mass or volumes in multiples. Even transgenic animal models have their
problems, not that they don't have their place in the research scheme of
things considering that humans can't be used in the same ways
experimentally.
>
> Charly Coughran
> ccoughran(a)DELETE_TO_RESPOND_UCSD.EDU

It is probably rare that low-carbing, insulin sensitizing meds, or
exercise could compensate for lost beta-cell mass of ~60% which is the
estimated loss in the typical type 2 DM at diagnosis. In the 5 years I
have been on the diabetes newsgroups there have been a few people who
managed to get the BG control down enough that their beta-cells have
enough insulin stored in their granules to have A1c levels under 5 which
may imply restoration of first phase insulin secretion. Blkbear maybe
one and he lost over 100 pounds. He also has an intensive exercise
routine after eating. Obese people can have beta-cell mass that is
greater than a normal glycemic, i.e., normal glucose and insulin
secretion. So someone like Blkbear probably has adequate beta-cell mass
for his new body size. As Old Al has said on occasions that a person
normal insulin resistance can have insulin secretion capacity over and
above that which is needed under most circumstances.

Frank
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