Diabetes: resulted from cellular mediated ?-cell destruction, often by


On the Endless Way of Finding a Cure

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Diabetes, though have long been documented, its impact
on public health is getting greater. This situation, in which drugs of
unclarified molecular mechanisms are still being
used as primary methods of
treatment, seems so hard to understand considering modern advancement in biology and medicine. Luckily recent
development of molecular biology and genetics have shed some light on uncovering
underlying mechanism of diabetes and how
drugs work in coordination with body’s metabolic and signaling network to
correct this condition.

Little History

Described by an ancient Egyptian manuscript from
approximately 1500 BCE, diabetes is now prevailing significantly throughout the
world. The Ancient Greek physician Aretaeus of
Cappadocia (fl. 1st century CE)4 was believed to give the first complete
clinical documentation, who also mentioned the excess amount of urine in the
patients.3 Since then, a series of milestones discoveries have provided a
scientific framework for understanding the metabolic syndrome.

Major milestones include:45

Development of Metformin in 1922 for treatment of type 2 Diabetes4

Development of the long-acting insulin NPH in the 1940s by Novo-Nordisk2

Reintroduction of the use of biguanides for Type 2 diabetes in the late
1950s. The initial phenformin was withdrawn worldwide (in the U.S. in 1977) due
to its potential for sometimes fatal lactic acidosis, and metformin was first
marketed in France in 1979, but not until 1994 in the US.4

Invention of amino acid sequencing method and the sequencing of insulin’s
two peptides (by Sir Frederick Sanger’s Nobel Prize winning work).10

The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and
Solomon Berson (gaining Yalow the 1977 Nobel Prize in Physiology or

The three-dimensional structure of insulin (PDB: 2INS?)4

Dr. Gerald Reaven’s identification of the constellation of symptoms now
called metabolic syndrome in 19884

Identification of the first thiazolidinedione as an effective insulin
sensitizer during the 1990s4

Categories of

Today’s medical science categorize
diabetes into 3 major groups, type 1, type 2 and other specific types related
to genetic defects of the glucose pathway components.101

Type 1 Diabetes

Type 1 diabetes resulted from cellular
mediated ?-cell destruction,
often by autoimmunity, while insulin receptor may remain fully functional.101
Some patients have permanent insulinopenia and are prone to ketoacidosis, but
have no evidence of autoimmunity.101 This condition called idiopathic
diabetes, are also categorized as type 1 diabetes.

Though caused directly by apparent
tissue damage, the precise origins of type 1 diabetes are largely unknown101,
as it requires a deeper understanding of autoimmunity. All patients eventually
become dependent on insulin for survival.101 In the end stage of type 1
diabetes, very low or even no plasma C-peptide can be observed, resulting in
little or no insulin secretion.101 Lifetime administration of insulin
products can effectively suppress the symptom to an extent allowing patients to
live to their normal life expectancy.102

Type 2 Diabetes

In contrast, type 2 diabetes is
caused by deficient response of glucose-controlling system to insulin.101 The
patients have relative rather than absolute insulin deficiency in this kind of
cases. From predominantly insulin resistance with relative insulin deficiency
to predominantly an insulin secretory defect with significant insulin
resistance, are all within the range of the type 2 category.101 Its frequency varies
in different racial/ethnic subgroups. It is often associated with a strong
genetic predisposition, more so than is the autoimmune form of type 1
diabetes.101 However, the genetics of this form of diabetes are complex and
not clearly defined.101,102

Patients with this kind of diabetes develop their hyperglycemia slowly but
hard to find and control101. Astonishingly we are still relying on metformin,
an ‘ancient’ drug, as one of a few drugs for this condition. According to American
Diabetes Association Standards of Medical Care in Diabetes106 and European Association
for the Study of Diabetes, metformin is the only recommended first-line therapy
for type-2 diabetes. Our current knowledge about metformin molecular mechanism
is limited but clear evidence of the molecule acting as a multi-pathway
metabolic regulator.103,107,301

Other Than Type 1 and Type 2 Diabetes

Several other forms of diabetes are
associated with genetic defects, or injuries to the pancreas. This category
include genetic defect of the ?-cell, genetic defects in insulin action, diseases of the exocrine
pancreas, endocrinopathies (excess hormones that antagonize insulin action),
drug- or chemical-induced diabetes, infections, uncommon forms of
immune-mediated diabetes (the stiff-man syndrome and the anti-insulin receptor
autoimmunity, formerly termed type B insulin resistance).101

New Advancements, New Hope

Recent Developments
in Type 1 Diabetes

It seems straightforward to treat
type 1 diabetes simply with insulin. But recent studies show in some cases it
is the gluten in foods has a close link to the autoimmune response that damages
?-cell.202,205,207,208,201 Gluten tends
to cause loss of a kind of proteins, Zonulin202,207, which constitutes tight
junctions between intestinal epithelium cells. This loss of Zonulin, in certain
people, can cause severe damage to the intestinal lining, letting gluten to
enter the bloodstream directly and then comes autoimmunity.206 Patients
having pathologic pathway can be successfully treated by removing gluten from
their daily diet without using insulin.201 This discovery shows how little we
know about its original cause and further researches are needed to validate the
direct link between gluten and cell damage.

Metformin: One Simple
Molecule, Several New Discoveries, One Long Quest

On the year of 1957, Jean Stern
introduced biguanides to diabetes treatment.301 The biguanides successfully
avoid toxicity and side-effects of other guanide species. Metformin was chosen
for further clinical development based on animal experiments data, followed by
two more potent molecules from the same family-phenformin and buformin.

However, phenformin and buformin were
soon found to have severe side-effects, especially lactic acidosis, therefore
were withdrawn from medical use.302 Worldwide use of metformin was
significantly affected since it also belongs to biguanides family.301
Metformin became available in the British National Formulary in 1958. It was
sold in the UK by Rona, a subsidiary of Aron Laboratories. Metformin was
approved in Canada in 1972 but did not receive approval by the US FDA until
1994301, partly due to the concern for its safety after the withdraw.

Years later a research from the
United Kingdom Prospective Diabetes Study (UKPDS) helped regain confidence in
the drug. Giving the strongest evidence of safety and effectiveness, the
research revealed the benefits of metformin in reducing cardiovascular
mortality and increasing the overall survival rate of obese diabetic
patients.301,303 Along with other convincing data analysis corroborating metformin’s
medical viability and incomparable benefits.304,305

Now as research of metformin’s
molecular mechanism accumulate, we are finally able to draw the framework of
the drug’s unique interaction with cell metabolism pathways. Although the exact
target of the drug on molecular level remains unidentified306, the primary
effect of metformin is mostly by mild inhibition of mitochondrial respiratory-chain
complex 1307. Metformin’s maximum inhibitory effect on complex 1 is about 40%
compared to about 80% of the reference inhibitor rotenone.307 This causes AMP/ATP
ratio to rise. AMP is an allosteric activator of tumor suppressor
serine/threonine kinase 11 (STK11/LKB1) and CaMKK?, and these two upstream
kinases phosphorylate Thr172 of AMP-activated protein kinase’s (AMPK) ? subunit, activating it.308 AMPK is a phylogenetically
conserved serine/threonine protein kinase viewed as a fuel gauge monitoring
systemic and cellular energy status and which plays a crucial role in
protecting cellular functions under energy-restricted conditions.306 Interestingly
recent discoveries also find ADP. Therefore ADP/ATP ratio could directly
regulate AMPK’s ? subunit,
too.309,310 The whole process in all switches cells from anabolic to
catabolic state.

Fig. 1. The
mitochondrial respiratory-chain complex 1 is the primary target of metformin.306
Due to its high acid dissociation constant (pKa=12.4) metformin exists in a
positively charged protonated form under physiological conditions and, as a
result, can only marginally cross the plasma membrane by passive diffusion.
Thus, its intracellular transport is mediated by different isoforms of the
organic cation transporters (OCT) depending on the tissue considered (e.g.,
OCT1 in liver or OCT2 in kidney).306

Maida et al. discovered
that metformin acutely increases plasma levels of glucagon-like peptide 1
(GLP-1) and induces islet incretin receptor gene
expression through a mechanism that is dependent on peroxisome
proliferator-activated receptor (PPAR)-?.315

However, a growing body of evidence from clinical studies and
animal models suggests that the primary function of metformin is to decrease
hepatic glucose production312, mainly by inhibiting gluconeogenesis313,314.

The improvement in insulin
sensitivity by metformin could be ascribed to its positive effects on insulin
receptor expression and tyrosine kinase activity.311

Conclusion and

Jean Sterne noted in the first
publication on metformin that “It metformin is well-tolerated in man, at
therapeutic doses, but its mechanism of action and its ultimate place in the
management of diabetes requires further study.”301 This miracle drug still
has huge potential even by today’s standard. After 90 years and many new
discoveries on its biological function, metformin never stops giving us surprises
since its first synthesis in 1927. Its exact mechanism is the core to
understand diabetes and will yield unimaginable medical value once clarified by
structural biology.



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