ADDIS ABABA UNIVERSITY

COLLEGE OF HEALTH SCIENCE

SCHOOL OF MEDICAL LABORATORY SCIENCE

MSc. IN CLINICAL CHEMISTRY

ADVANCED CLINICAL CHEMISTRY AND ENZYMOLOGY INDIVIDUAL ASSIGNMENT

Module code: CLCH652

Title: Anti- diabetic drugs

Name ID Number

Habtamu Molla GSR/1888/15

ASSIGNMENT FOR THE PARTIAL FULFILLMENT OF THE COURSE ADVANCED

CLINICAL CHEMISTRY AND ENZYMOLOGY; SUBMITTED TO: Dr. Mistire Wolde (Ph. D,
Associate professor).

Submission Date: 12/04/ 2023.

Addis Ababa, Ethiopia, 2023.

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Acknowledgment

Firstly, I would like to say thanks to Almighty GOD and his mother for giving me all things and
protecting me from everything. Secondly, I would like to express deep gratitude to my respective
instructor Dr. Mistire Wolde (Ph.D., Associate professor.), who gave me the chance to do this assignment
and for her help by addressing clear information on the way and methods we used to do this assignment.
And also, I would like to express my heartfelt thanks to all my friends who helps me by showing different
methods and also giving comments on my assignment.

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Tables of contents

Table of Contents
Acknowledgment........................................................................................................................................i
Tables of contents.......................................................................................................................................ii
List of figures..............................................................................................................................................iii
1. Anti-diabetic drugs..............................................................................................................................1
1.1. Introduction.................................................................................................................................1
1.2. Anti-diabetics drugs and their mechanism of actions..................................................................2
1.2.1. Biguanides (metformin).......................................................................................................2
1.2.2. Sulfonylureas.......................................................................................................................2
1.2.3. Alpha-glucosidase inhibitor..................................................................................................3
1.2.4. Meglitinides( glindes)...........................................................................................................3
1.2.5. Thiazolidinediones (TZD)....................................................................................................3
1.2.6. Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibitors.......................................4
1.2.7. DPP-4 inhibitors...................................................................................................................4
1.2.8. Insulin..................................................................................................................................4
1.3. Anti-diabetic drugs and mechanisms of resistance......................................................................6
1.3.1. Metformin’s.........................................................................................................................6
1.3.2. Sulfonylureas.......................................................................................................................6
1.3.3. Alpha-glucosidase inhibitors................................................................................................7
1.3.4. Thiazolidinediones (TZD)......................................................................................................7
1.3.5. Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibitors.......................................8
1.3.6. DPP-4 inhibitors...................................................................................................................8
1.3.7. Insulin..................................................................................................................................8
1.4. Laboratory diagnosis of Resistance of ant diabetic drugs........................................................9
Summary...................................................................................................................................................10
References.................................................................................................................................................11

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List of figures

Figure 1: Mechanism action of insulin........................................................................................................5

Figure 2: Mechanism action of ant diabetic drugs.....................................................................................5
Figure 3: Target tissues and mechanism of action of current anti-diabetic drugs.........................................6

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 1. Anti-diabetic drugs
1.1. Introduction
Diabetes mellitus is a major chronic and metabolic health problem, characterized by an elevated
level of blood sugar for a persistent period of time. It comprises a group of metabolic diseases
resulting in hyperglycemia, either because the body does not produce enough insulin, or cells do
not respond to the insulin. Since Diabetes is a complex chronic illness, it requires continuous
medical care with multifactorial risk-reduction strategies (1).

Thee major types of diabetes mellitus are: Type 1 diabetes, Type 2 diabetes, and gestational diabetes.
Type 1 diabetes accounts for 5–10% of all case of diabetes. Type 1 diabetes is also known as insulin-
dependent diabetes mellitus, or youthful-onset, since it is diagnosed in children, teenagers, and young
adults; however, in the previous decade, it has been discovered that it can develop at any age. In type 1
diabetes, beta cells are unable to produce insulin in the pancreas because of the autoimmune response of
the body, where antibodies destroy beta cells, causing a lack of insulin (2). Overall, type 2 diabetes is
the most common, accounting for around 85–90% of all cases; it is also known as non-insulin-
dependent or adultoutset diabetes. It is most often diagnosed in people aged 45 years or older,
but is also found in younger generations. In type-2 diabetes, the production of insulin takes place
in the β cells of the pancreas, but insulin receptors or insulin-responsive cells in the cell
membrane do not respond normally to insulin. There is a poor response or no response to
receptors, known as “insulin resistant”, thus increasing blood glucose levels (3). Gestational
diabetes is another type of diabetes, observed in pregnant women, usually during advanced
stages of pregnancy. Treatments of gestational diabetes include special dietary plans and regular
physical activity. Sometimes, a few anti-diabetic drugs required to maintain normal blood
glucose levels (4)

Thousands of new anti-diabetes drugs are synthesized each year, but it is very difficult to get rid
of this deadly disease. Diabetes has a major consequence on fatality and mortality, and is a
worldwide non-communicable disease. According to the International Diabetes Federation (IDF)
Diabetes Atlas data, diabetes currently affects an estimated 451 million people in the world in
2017, and if this trend continues, this will rise to 693 million by the end of 2045 (5). There are
several complications of diabetes, such as cardiovascular disease, retinopathy, nephropathy,
neuropathy, food disorders, complications during pregnancy, dental disease, kidney disease, etc.
Diabetes can also interfere with wound healing. Some other complications of diabetes are
ketoacidosis, hyperosmolar coma, reduced immunity to pneumonia and influenza (6).

Insulin is also called the principal hormone, which controls blood glucose levels in our body by
transferring glucose from the blood to the tissue. Insulin production takes place in the beta cells
of the pancreas, and is stored in the body in units of six molecules; the active form is a monomer.
The main action of insulin is to control the circulating blood glucose coming from carbohydrates

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throughout the body, especially that entering tissues via insulin receptors or insulin-responsive
cells. If beta cells are not able to synthesize insulin, then type-1 diabetes occurs, while type-2
diabetes occurs if insulin receptors or insulin-responsive cells cannot respond to insulin (7).

1.2. Anti-diabetics drugs and their mechanism of actions

If someone can't maintain your target blood sugar level with diet and exercise, health care
provider may prescribe diabetes medications that help lower glucose levels, or health care
provider may suggest insulin therapy. Medicines for type 2 diabetes include the following.

1.2.1. Biguanides (metformin)

Biguanides improve cellular response to natural insulin, decreases the absorption of glucose from
the intestine and reduces the amount of glucose produced by liver. Biguanides reduce hepatic
glucose output by decreasing gluconeogenesis and stimulating glycolysis. They increase the
insulin signaling by increasing the insulin receptor activity. Different agents in this category are
Metformin, Phenformin, and Buformin (8).
Phenformin and Buformin were used clinically, but their relationship to lactic acidosis led to
their withdrawal from the market in most countries. Metformin is the most widely prescribed
oral agent for type 2 diabetes mellitus (T2DM) throughout the world due to of its proven efficacy
on glycemic control both as monotherapy and in combination with many other available agents
(8,9). Metformin is an insulin-sensitizing drug that exerts its anti-hyperglycemic effects by
blocking liver gluconeogenesis through regulation of the gluconeogenic flux, rather than direct
inhibition of gluconeogenesis by gene expression. Some studies suggest that metformin acts as
an inhibitor of complex I of the electron transport chain, leading to activation of AMP-activated
protein kinase (AMPK) sensitive signaling. AMPK acts as a regulator of glucose and lipid
metabolism, as well as of cellular energy, through phosphorylation of some key proteins. Other
studies reported that metformin increases plasma levels of glucagon like peptide-1 (GLP-1),
which is an incretin hormone with anti-hyperglycemic properties; this stimulates islet incretin
receptor gene expression, through a mechanism that is dependent on peroxisome proliferator-
activated receptor α (PPARα)( 10,11).

1.2.2. Sulfonylureas
Sulfonylureas exert their action by binding directly on pancreatic β cells through binding to the
cytosolic face of sulfonylurea receptor 1 (SUR1), which is part of the ATP-sensitive potassium
channel (12). This closes the channel, thus preventing potassium efflux and depolarizing the
plasma membrane, leading to the opening of the local voltage-dependent calcium channels,
increasing the influx of calcium, and activating calcium-dependent signaling protein that lead to

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insulin exocytosis. Sulfonylureas may also have extra-pancreatic effects, one of which is to
increase tissue sensitivity to insulin, but the clinical importance of these effects is minimal. They
are classified as first-generation (such as tolbutamide and chlorpropamide) and second-
generation (such as glibenclamide, gliclazide, glipizide, and glimepiride)( 13).

1.2.3. Alpha-glucosidase inhibitor

Alpha-glycosidase enzymes found in the brush border of enterocytes lining the intestinal villi,
breakdown carbohydrates to monosaccharide’s before absorption in the intestine (14). Therefore,
inhibitors of intestinal of α-glycosidase enzymes influence the rate of digestion of carbohydrates
and disaccharides by competitively and reversibly inhibiting α-glycosidase present in the brush
border membrane of enterocytes that line the intestinal villi. Thus, the digestion of carbohydrates
and absorption of monosaccharaides in the proximal jejunum are reduced or incomplete in the
distal jejunum and ileum which lead to a drop in postprandial plasma glucose levels. The delay
in the absorption of glucose by these inhibitors allow the pancreatic β-cell more time to augment
insulin secretion in response to the increase in plasma glucose level (15, 16)

1.2.4. Meglitinides( glindes)

Meglitinides (glinides) have a similar mechanism of action with sulfonylureas being an insulin
secretagogues and also get their name from the meglitinide moiety of glibenclamide. However,
this moiety acts independent of the sulfonyl moiety to release insulin. Like the sulfonylureas, the
insulinotropic action of repaglinide is mediated via adenosine triphosphate (ATP)-dependent
potassium channels. Repaglinide stimulates insulin secretion by blocking ATP-dependent
potassium channels (KATP) of the pancreatic β-cell, where inhibition of KATP channels results
in membrane depolarization and calcium influx through voltage-gated calcium channels. These
events lead to an increase in intracellular calcium and subsequent exocytosis of insulin-containing
granules. Repaglinide binds to the sulfonylurea receptor SUR1 and it seems to have also a separate
distinct binding site on β-cells. Moreover, molecular studies have shown that the binding site of
repaglinide is different from that of glibenclamide and nateglinide (12)

1.2.5. Thiazolidinediones (TZD)

Thiazolidinediones are peroxisome proliferator–activated receptor-γ (PPAR-γ) activators whose
mechanisms of action are enhancement of skeletal muscle insulin sensitivity and reduction in
hepatic glucose production. They do not increase the risk of hypoglycemia and have a more
durable effect than metformin or SUs . PPAR-γ agonists activate the differentiation of pre-
adipocytes into new small insulin-sensitive adipocytes which leads to decrease in the levels of
free fatty acids in circulation. Consequently, this reduces ectopic lipid accumulation in skeletal
muscle and liver and rebalances the glucose–fatty acid cycle by favoring glucose utilization.
Finally, it leads to restricting availability of free fatty acids as an energy source for hepatic
gluconeogenesis (12, 17)

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 1.2.6. Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibitors

This group includes Canagflozin, Empagliflozin, and Dapagliflozin. Sodium-dependent glucose

co-transporters (SGLTs) are vast group of proteins that facilitate the movement of glucose and
sodium across the plasma membrane of cells in many tissues (18). Two members of SGLT
family mediate reabsorption of glucose in the kidney. The SGLT2 inhibitors ameliorate
hyperglycemia by inhibiting SGLT2 which leads to glycosuria and lowering of blood glucose
because SGLT1 (which is the low-capacity, high-affinity transporter) cannot reabsorb all of the
filtered glucose. However, because of physiological changes that occur in response to SGLT2
inhibitor administration, these agents only reduce renal glucose reabsorptive capacity by up to
50%(19).

1.2.7. DPP-4 inhibitors

Dipeptidyl peptidase 4 (DPP-4) inhibitors include sitagliptin, vildagliptin, saxagliptin,
linagliptin, and alogliptin. The action of DPP-4 inhibitors causes elevation of circulating levels
of incretin hormones, notably GLP-1 and GIP. GIP and GLP-1 are rapidly degraded by DPP-4
and exists both free in the circulation and also attached to endothelial cells and widely expressed
in human tissues, including the intestine and portal system (77). GLP-1 and GIP are generally
inactivated almost immediately following secretion, and have half-lives of less than 2 min and 5-
7 min, respectively (20).

1.2.8. Insulin
Exogenous insulin is used in the treatment of diabetes, primarily type 1, to supplement deficient
insulin synthesis in pancreatic beta cells. Once injected, it acts similarly to its endogenous
counterpart, helping to normalize glucose levels and metabolism by activating glucose
transporters in the cell membrane leading to absorption of glucose into the cell. Insulin is a
polypeptide hormone produced by the β-cells of islets of Langerhans of pancreas and it plays a
vital role in the metabolism of carbohydrate, fat and protein. Insulin is considered as anabolic
hormone, as it promotes the synthesis of glycogen triacylglycerols and protein (21). Insulin
exerts all of its known physiological effects by binding to the insulin receptor (INSR) on the
plasma membrane of target cells. INSR is a heterotetrameric receptor tyrosine kinase formed
from two extracellular α subunits, which bind insulin, and two membrane-spanning β subunits,
each of which contains a tyrosine kinase domain. There are two INSR isoforms, A and B, but the
B isoform is much more specific for insulin; is the primary isoform expressed in differentiated
liver, muscle, and WAT; and is thus thought to mediate most metabolic effects of insulin (22). 

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Figure 1: Mechanism action of insulin

Figure 2: Mechanism action of ant diabetic drugs

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Figure 3: Target tissues and mechanism of action of current anti-diabetic drugs.

1.3. Anti-diabetic drugs and mechanisms of resistance

The exact mechanism of insulin resistance is not fully understood, but there are several factors that have
been implicated (17, 22).

1.3.1. Metformin’s
Genetic factor, reduce drug uptake, impaired hepatic metabolism and insulin resistance are main
mechanism of resistance of metformin. Some genetic variants may affect the expression or
activity of proteins involved in metformin's mechanism of action, leading to decreased sensitivity
or resistance to the drug. Metformin is taken orally and must be absorbed into the bloodstream
to be effective. Factors that affect the absorption and distribution of the drug, such as
gastrointestinal problems or drug interactions, can reduce its efficacy. Metformin is primarily
metabolized in the liver, and liver dysfunction or disease can reduce its efficacy by impairing its
metabolism. Insulin resistance: Metformin's efficacy is dependent on insulin sensitivity in the body's
tissues, particularly in muscle tissue. Insulin resistance can reduce the drug's effectiveness by decreasing
glucose uptake and utilization by cells (9).

1.3.2. Sulfonylureas
Beta-cell dysfunction, loss of beta cell mass, genetic factors, insulin resistant, other medications
are the main mechanism of resistance of sulfonylureas. Sulfonylureas work by stimulating
insulin release from the beta cells in the pancreas. Over time, beta cells may become damaged or

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dysfunctional, which can reduce their ability to release insulin in response to sulfonylureas. In
some cases, beta cells may be destroyed or lost due to autoimmune or other mechanisms. This
can reduce the total amount of insulin that can be released in response sulfonylureas. Some
individuals may have genetic variants that affect the expression or activity of proteins involved
in the sulfonylurea mechanism of action, leading to reduced sensitivity or resistance to the drug.
Insulin resistance can reduce the effectiveness of sulfonylureas by reducing the ability of insulin
to stimulate glucose uptake and utilization in cells. Some medications, such as corticosteroids
and certain antipsychotic drugs, can interfere with the action of sulfonylureas and reduce their
effectiveness (17).

1.3.3. Alpha-glucosidase inhibitors

There are several potential mechanisms of resistance to alpha-glucosidase inhibitors, although
they are not well understood. One possible mechanism of resistance is the development of
compensatory mechanisms that increase the activity of other enzymes involved in carbohydrate
digestion, such as pancreatic alpha-amylase. This could result in increased carbohydrate
digestion and decreased effectiveness of alpha-glucosidase inhibitors. Another possible
mechanism of resistance is the Downregulation or alteration of the alpha-glucosidase enzymes
themselves. Over time, prolonged exposure to alpha-glucosidase inhibitors could lead to changes
in the expression or activity of these enzymes, which could result in decreased sensitivity to the
medication. Resistance to alpha-glucosidase inhibitors can limit their effectiveness in the
treatment of type 2 diabetes, and may require the use of alternative medications or combination
therapy to achieve glycemic control. However, more research is needed to fully understand the
mechanisms of resistance to these medications (22).

1.3.4. Thiazolidinediones (TZD)

One of the mechanisms of resistance to thiazolidinediones (TZDs) is the Downregulation of
PPAR-gamma, the nuclear receptor that is activated by TZDs. Over time, prolonged exposure to
TZDs can lead to a decrease in the expression of PPAR-gamma in tissues, particularly in adipose
tissue. This can result in a reduced response to TZDs and a decreased ability of the medication to
improve insulin sensitivity and lower blood glucose levels. Another mechanism of resistance to
TZDs is the development of insulin resistance. As insulin resistance worsens, the ability of TZDs
to improve insulin sensitivity and lower blood glucose levels may be compromised. Furthermore,
changes in the expression of other genes and proteins involved in glucose and lipid metabolism
can also contribute to resistance to TZDs. For example, increased expression of enzymes
involved in glucose production in the liver and decreased expression of enzymes involved in
glucose uptake and storage in adipose tissue can reduce the effectiveness of TZDs. Resistance to
TZDs can limit their effectiveness in the treatment of type 2 diabetes, and may require the use of
alternative medications or combination therapy to achieve glycemic control (26).

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 1.3.5. Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibitors
Resistance to SGLT2 inhibitors can develop through a variety of mechanisms, although they are
not yet fully understood. One possible mechanism of resistance is upregulation of glucose
transporters, particularly GLUT1 and GLUT2, in the renal proximal tubules. This could increase
glucose reabsorption and offset the glucose-lowering effects of SGLT2 inhibitors. Another
potential mechanism of resistance is the activation of compensatory mechanisms, such as the
renin-angiotensin-aldosterone system (RAAS), which could increase renal glucose reabsorption
and decrease the effectiveness of SGLT2 inhibitors. Additionally, genetic variations in SGLT2
expression or function could contribute to variability in response to SGLT2 inhibitors.
Resistance to SGLT2 inhibitors could limit their effectiveness in the treatment of type 2 diabetes
and may require the use of alternative medications or combination therapy to achieve glycemic
control. However, further research is needed to fully understand the mechanisms of resistance
and to develop strategies to overcome it (25, 27).

1.3.6. DPP-4 inhibitors

DPP-4 enzyme activity, Insulin resistance and other medications are the mechanisms of
resistance of DPP-4 inhibitors. DPP-4 enzyme may become less sensitive to inhibition by DPP-4
inhibitors, which can reduce their effectiveness in increasing the levels of active incretin
hormones. Insulin resistance can reduce the ability of incretin hormones to stimulate insulin
secretion and lower blood glucose levels. This can limit the effectiveness of DPP-4 inhibitors in
individuals with insulin resistance. Some medications, such as corticosteroids and certain
antipsychotic drugs, can interfere with the action of DPP-4 inhibitors and reduce their
effectiveness (22).

1.3.7. Insulin
There are several mechanisms of insulin resistant some of them are: The first one is genetics:
Insulin resistance may be partially inherited, with certain genetic variants associated with an
increased risk of developing the condition. The second one is Obesity: Obesity is a major risk
factor for insulin resistance. Excess fat tissue can release substances called adipokines, which
can interfere with insulin signaling and lead to insulin resistance. The third one is Inflammation:
Chronic inflammation can also interfere with insulin signaling and lead to insulin resistance.
The fourth one is Age: Insulin resistance tends to increase with age, possibly due to changes in
metabolism and hormonal balance. The fifth factor is Physical inactivity: Lack of exercise can
reduce insulin sensitivity and contribute to the development of insulin resistance. Another factor
is Dietary factors: A diet high in processed and sugary foods can contribute to insulin resistance.
And also Advanced disease: In advanced cases of type 2 diabetes, the body's ability to produce
and respond to insulin may be severely compromised, making it difficult for metformin to
adequately control blood glucose levels (23,24).

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 1.4. Laboratory diagnosis of Resistance of ant diabetic drugs
Diagnosing resistance to anti-diabetic drugs typically involves measuring blood glucose levels
and assessing glycemic control in patients receiving the medication (28, 29). In the laboratory
setting, there are several tests that can be used to assess drug resistance, including:

I. Hemoglobin A1C (HbA1c): HbA1c is a blood test that measures the average blood glucose level
over the previous 2-3 months. It provides a long-term indicator of glycemic control and can be
used to monitor response to anti-diabetic therapy.
II. Glucose tolerance test (GTT): The GTT involves measuring blood glucose levels before and after
a standardized oral glucose load. This test can be used to assess insulin sensitivity and detect
impaired glucose tolerance, which may indicate resistance to anti-diabetic medications (30).
III. Insulin resistance assays: These tests measure insulin sensitivity and resistance using
various techniques, such as the euglycemic hyperinsulinemic clamp or the homeostatic
model assessment of insulin resistance (HOMA-IR). These tests can be used to assess the
effectiveness of insulin-sensitizing medications, such as thiazolidinediones (31).
IV. Genetic testing: Genetic testing can be used to identify mutations or variations in genes
associated with drug metabolism or response. For example, genetic testing can identify variations
in the SGLT2 gene that may impact response to SGLT2 inhibitors.
V. Urine tests: Urine tests can be used to monitor renal function and assess the effectiveness of
SGLT2 inhibitors, which work by blocking glucose reabsorption in the kidneys. Tests such as
urine glucose and urine ketone measurements can provide information about glucose excretion
and ketone production, respectively.

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 Summary
Diabetes is a complex chronic illness; it requires continuous medical care with multifactorial risk-
reduction strategies. The major types of diabetes are: Type one DM, Type two DM and gestational DM.
The major complications of diabetes are cardiovascular disease, retinopathy, nephropathy, neuropathy,
food disorders, and complications during pregnancy, dental disease, and kidney disease. The main anti
diabetics drugs used for treatments of diabetes mellitus are: Metformin, Sulfonylureas, Alpha –
glucosidase inhibitors, Glinds, Thiazolidinediones (TZD), Sodium dependent glucose co transporters
(SGLT2) inhibitors, DPP 2 inhibitors and insulin.

Anti-diabetic drugs works based on different mechanisms of actions: Biguanides (metformin) Improve
cellular response to natural insulin, decreases the absorption of glucose from the intestine and reduces
liver glucose output. Sulfonylureas bind directly on pancreatic β cells leading to insulin exocytosis. Alpha
–glucosidase inhibitors works based on Inhibition of intestinal of α-glucosidase enzymes present in the
brush border membrane of enterocytes that line the intestinal villi. Thiazolidinediones (TZD) work based
on Peroxisome proliferator–activated receptor-γ (PPAR-γ) action on skeletal muscle. It enhances skeletal
muscle insulin sensitivity and reduction in hepatic glucose production. Meglitinides (glindes) Stimulates
insulin secretion by blocking ATP-dependent potassium channels (KATP) of the pancreatic β-cell,
leading to exocytosis of insulin-containing granules. Sodium dependent glucose co transporters (SGLT2)
inhibitors works based on Inhibition of SGLT2 which leads to glyco-suria and lowering of blood glucose
by de-creasing glucose reabsorptive capacity. Dopamine D2 receptor agonist (DPP-2) reduces insulin
resistance leading to an increase in glucose disposal and a reduction in hepatic glucose production. Insulin
works based on stimulation of glucose uptake occurs through translocation of GLUT4-containing storage
vesicles (GSVs) to the plasma membrane. The resultant increase in intracellular glucose-6-phosphate
production, together with a coordinated dephosphorylation of glycogen metabolic proteins, enables net
glycogen synthesis.

The mechanism of resistance of anti-diabetics drugs are the following: Metformin’s resistance related to
genetic factor, reduce drug uptake, impaired hepatic metabolism and insulin resistance. Sulfonylureas
resistance related to Beta-cell dysfunction, loss of beta cell mass, genetic factors, insulin resistant, other
medications. Sulfonylureas work by stimulating insulin release from the beta cells in the pancreas. Alpha
–glucosidase inhibitors develop compensatory mechanisms that increase the activity of other enzymes
involved in carbohydrate digestion, such as pancreatic alpha-amylase. The mechanism of resistance to
thiazolidinediones (TZDs) is the Downregulation of PPAR-gamma, the nuclear receptor that is activated
by TZDs. Sodium dependent glucose co transporters (SGLT2) resistance is due to upregulation of glucose
transporters, particularly GLUT1 and GLUT2, in the renal proximal tubules.

Diagnosing resistance to anti-diabetic drugs involves measuring Hemoglobin A1C (HbA1c, Glucose
tolerance test (GTT), Insulin resistance assays, genetic testing and urine tests.

10
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