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Type 2 Diabetes Mellitus- Disease, Diagnosis and Treatment

Yingzheng Zhao#, Guangcui Xu#, Weidong Wu and Xianwen Yi*
School of Public Health, Xinxiang Medical University, Xinxiang, Henan Province, PR China

Type 2 diabetes mellitus (T2DM) is a fast-growing disease and a leading global public health concern. Multiple
complications are associated with T2DM. Patient education with lifestyle modifications
and pharmacotherapy are main methods for treatment of patients afflicted with T2DM.
Lifestyle interventions are effective strategies but usually persist for a short term whereas T2DM patients with
long-term treatment still present challenges in many cases. In this review, we have briefly summarized recent
progress for T2DM diagnosis and treatment. We attempt to provide an outline for T2DM diagnosis
and treatment. In addition, we introduce Chinese herbal medicine as an alternate treatment for physicians and
T2DM patients.

based on plasma glucose criteria. The most

Introduction widely accepted T2DM diagnostic tests are the
Type 2 diabetes mellitus (T2DM) is a metabolic Fasting Plasma Glucose (FPG) and the Oral
disorder and typically results from excess of Glucose Tolerance Test (OGTT). Both FPG
caloric intake over energy expenditure. It is (diagnostic of diabetes at plasma glucose level
characterized by a progressive insulin ≥ 126 mg/dL or 7.0 mmol/L) and 2-hour OGTT
secretory defect due to insulin resistance, (diagnostic of diabetes at plasma glucose level
which increases the body’s demand for insulin ≥ 200 mg/dL or 11.1 mmol/L) are commonly
in order to retain glucose homeostasis. If used diagnostic tests. The advantages of FPG
pancreatic β-cells fail to secrete enough insulin are low cost and the popularity of automated
to compensate for increasing insulin demand, laboratory machines available. Although the
the blood glucose level will be elevated OGTT has long been established as one of the
gradually. Chronic hyperglycemia is associated diagnostic modalities for diabetes, compared
with long-term damage, dysfunction, and with FPG, it is less practical as a plasma glucose
failure of different organs, especially the eyes, test in clinical settings. In fact, the WHO
kidneys, nerves, heart, and blood vessels discouraged the use of the OGTT for the
resulting in increasing levels of morbidity and diagnosis of diabetes due to its inconvenience,
mortality. T2DM associated with poor lifestyle high cost, and poor reproducibility.
is a primarily factor leading to the progressive Blood HbA1c
reduction of physical activity and changes of Blood HbA1c is a favorable diagnostic tool for
dietary habits. As a consequence, a greater the following reasons. First, HbA1c
percentage of the population will become measurements can be carried out at any time
overweight and obese. T2DM is the one of the and do not require preparation by tested
most prevalent chronic diseases worldwide subjects. Second, its intraindividual biological
and one of the major public health challenges variability is low, hence with high
of the 21st century. The epidemic of T2DM in reproducibility. HbA1c is not influenced by
the United States and the rest of the world sudden glycemic variations
continue to grow rapidly; as many as 20 million and psychological stress. Third, it reflects the
people in the United States may have the mean blood glucose levels over the last 3
disease. The vast majority of patients with months. Thus, HbA1c can be measured
diabetes suffer from T2DM . approximately every 3 months to determine
Diagnosis of T2DM whether a patient’s targets for glycemic
Diagnostic criteria and common tests control have been reached and maintained.
Hyperglycemia is a major symptom in T2DM. Fourth, epidemiological analyses have
Other typical symptoms of T2DM include concluded that for every percentage point
polyuria, polydipsia, fatigue, weight loss and decrease in HbAlc level, there is a 25%
urine glucose. Diabetes is usually diagnosed reduction in diabetes-associated deaths, 35%
reduction in the risk of microvascular

complications and 18% reduction in combined cessation. Diet and regular exercise from
fatal and non-fatal myocardial infarction. In moderate to intense can improve glucose
2010, the American Diabetes Association levels in patients with T2DM and those at risk
(ADA) advocated HbA1 as a diagnostic criterion for developing obese and T2DM. Lifestyle
for diabetes. The ADA selected a result of 6.5% intervention is a proven strategy for reducing
as the cutoff value for T2DM diagnosis, diabetes incidence. Nevertheless, the
assessed by the development of diabetic intervention is considered effective only in the
retinopathy, which increases steeply at ≥ 6.5% short term but is difficult to adhere to in the
. This roughly corresponds to a fasting blood long run, thus limiting its effectiveness.
glucose concentration of 100–125 mg/dL, and Anti-diabetes pharmacotherapy
to a postprandial glucose concentration of The ultimate goal for the pharmacotherapy is
140–199 mg/dL. In 2011, the HbA1c test was to modify disease progression in a manner
endorsed by the WHO as a diabetes diagnostic preventing pathophysiological decline towards
test, provided that the measurements are β-cell dysfunction and long-term complications
performed by standardized HbA1c tests that associated with hyperglycemia. People should
passed the stringent quality assurance tests. be aware that all anti-diabetic drugs except
Since then, HbA1c has officially become a insulin require some degree of residual
diabetes diagnostic criterion. There are pancreatic β-cells to perform function. A single
drawbacks for HbA1c measurement. It is anti-hyperglycemic drug often suffices initially,
affected by erythrocyte conditions. For but a second drug with a different mechanism
patients suffering from anemia and of action usually is required with the disease
hemoglobin disorders, results of HbA1c testing progression. In advanced T2DM, insulin
are not reliable. In addition, the diagnostic intervention may be necessary. For
cutoff values of the HbA1c tests seem to convenience, oral agents are typically the first
depend on demographic, anthropometric, choice for the treatment of T2DM but oral
or laboratorymeasurements. For example, the delivery bears some drawbacks such as
China Guideline regarding T2DM in 2010 did frequent dosing, short half life, and low
not recommend the HbA1c test for the bioavailability. We outline major anti-diabetic
diagnosis of diabetes due to inconclusive drugs for their efficacy, safety and mechanisms
results in the Chinese population and the lack of action in the following pages. It is important
of a standardized HbA1c measurement for both clinicians and patients to obtain a
nationwide. Results of three studies from broad understanding of each class of oral
different population groups in Shanghai, agents so as to optimize diabetic control. In
Beijing and Qingdao, have found different addition, despite the availability of many oral
cutoff points of HbA1c for diabetes . Moreover, anti-diabetic agents, therapeutic efficacy in
it is reported that HbA1c fluctuations due to some of them is offset by side effects such as
genetic and biological variations coexist with weight gain and hypoglycemia. Furthermore,
medical complications and assay interference . treatment with glucose-lowering agents is
Treatment of T2DM generally characterized by loss of efficiency
Non-pharmacologic treatment over time, due to progressive β-cell
It is well-established that lifestyle plays a dysfunction. Thereby, there is an unceasing
crucial role in prevention and treatment of requirement for adjustment including agent
T2DM. The ADA endorses the education of dose, and/or agent type or a combination of
diabetes self-management. This education can different agents in all stages of the disease.
help the patient to obtain necessary Metformin: Metformin is one of the oldest but
knowledge and skills for self-care, manage the safest agents used in the treatment of
hyperglycemia and possible hypoglycemia, and T2DM. Metformin is the first choice of
make lifestyle changes. Primary non- recommended therapy for T2DM according to
pharmacological interventions mainly include the International Diabetes Federation Global
appropriate nutritional diet, Guideline for T2DM, in agreement with similar
regular physical exercise and smoking guidelines from the ADA, as well as the

European Association for the Study of Diabetes promotes weight gain. Many patients can
(EASD). Metformin exerts its effects primarily increase more than 2 kg after initiative
by reducing hepatic glucose output through medication. Furthermore, sulfonylureas are
inhibition of gluconeogenesis and has a associated with a higher cardiovascular risk
comparatively lesser effect increasing insulin than metformin likely due to impairment of
sensitivity. Hence, unlike insulin or endothelial function with increased risk for
sulfonylureas, metformin is primarily an ischemic complications . It is also noteworthy
antihyperglycemic agent, rather than a that some patients with an allergy to
hypoglycemic agent. As a result, metformin sulfonamide medications exhibit cross-
does not cause hypoglycemia. In addition, it reactivity with sulfonylureas.
does not cause weight gain due to its anorexic Glinides, nateglinide and replagnide are a new
effect. Weight gain can worsen the course of generation of sulfonylureas. They display
the disease in the long run. Metformin also similar effects as sulfonylreas by binding to the
modestly reduces plasma triglyceride sulfonylurea receptor and inducing
concentrations resulting from decreased depolarization of the β-cells. However, they
production of very low density lipoprotein and bind in a different manner to the sulfonylurea
has favorable effects on a number of receptor. They also have shorter half-lives than
cardiovascular risk factors such as lipids, body sulfonylureas. Therefore, they require more
weight, blood pressure and platelet function . frequent dosing. Glinides may possess a lower
Therefore, metaformin is particularly suitable propensity towards hypoglycemia.
for T2DM obese patients with cardiovascular GLP1 receptor agonists and DPP-4
diseases. Another advantage of metformin is inhibitors: Glucagon-like peptide 1 (GLP-1) is a
the reduction of mortality, as documented in 30-amino-acid peptide. It is an incretin
the UKPDS. The most common reported hormone produced by ileum and colon, and
adverse reaction to metformin therapy is released into the bloodstream. GLP-1 is
gastrointestinal upset including nausea, released in response to meal ingestion and
vomiting, anorexia and diarrhea. Thus, blood glucose concentration in a harmonized
metformin should be started at a low dose at fashion for hormone release . GLP-1 also exerts
first (500 mg PO bid). Another drawback to an anti-diabetic effect by delaying gastric
metformin is that it cannot be used when emptying, suppressing glucagon release and
kidney function is impaired indicated by a increasing glucose-stimulated insulin release.
glomerular filtration rate (GFR) lower than 60 The resulting effect of GLP-1 is to curb
mL/min. postprandial hyperglycemia, but its half-life
If metformin is poorly tolerated or the after secretion into the blood is very short.
monotherapy results in an HbA1c value that is Thus, two strategies are used to overcome this
still elevated for 3 months, then treatment can problem. A) incretin mimetic such as
be amplified with the addition of a second anti- liraglutide, approved by FDA in 2010, is a long
diabetic drug. acting GLP-1 degradation enzyme analogue for
Sulfonylureas: Sulfonylurea binds to the treatment of T2DM. It has a long half-life of 14
sulfonylurea receptor on the surface of the β- h and is resistant to dipeptidyl peptidase-4
cells and inhibits potassium efflux, thus (DPP-4) degradation. B). GLP-1 degradation
depolarizing the β-cells and facilitating insulin enzyme inhibitors like DPP-4 is the newest
release. Because sulfonylurea acts by class of oral agents for the treatment of T2DM.
stimulating insulin release from β-cells, DPP-4 inhibitors such as vildagliptin, sitagliptin,
patients without a sufficient number of β-cells, saxagliptin, linagliptin and alogliptin inhibit the
such as those with later stages of T2DM, do not enzymatic degradation of GLP-1. As a
respond to the medication. An advantage of consequence, GLP-1 concentration increases,
sulfonylureas is its low cost to patients. Its leading to decreased postprandial glucose
disadvantage is that sulfonylurea treatment level. DPP-4 inhibitors and incretin mimetics do
carries a risk of hypoglycemia, especially in not carry a risk of hypoglycemia, as these drugs
elderly patients. In addition, the drug

seldom alter insulin secretion levels during insufficiency, an increased risk of bone
fasting state. fractures, a rare side effect of hepatotoxicity
Another major advantage of the DPP-4 and possibly, an increased incidence of bladder
inhibitors is to retain body weight when the cancer. A meta-analysis suggested that
patient is mal-nourished or under weight. DPP- patients using rosiglitazone may have an
4 inhibitors are approved for both increase in the risk of myocardial infarction and
monotherapy and co-deliver with metformin death from cardiovascular causes .
and thiazolidinediones. DPP-4 inhibitors have SGLT-2 inhibitors: Sodium-glucose co-
gastrointestinal side effects and may cause transporter 2 (SGLT2) inhibitors are another
urticaria . Moreover, cost of DPP-4 inhibitors is new class of anti-diabetic drug with an
high, a major limiting factor for their clinical insulinindependent mechanism. The SGLT2 is a
use. transporter found in the kidney proximal
Likewise, DPP-4 inhibitors can be used for tubule and is responsible for approximately
inhibiting Glucosedependent Insulinotropic 90% of renal glucose reabsorption. The SGLT2
Polypeptide (GIP). GIP is a 42-amino-acid inhibitors like dapagliflozin are highly selective
peptide derived from ProGIP, a large protein. SLGT2-inhibitors and reduce reabsorption of
GIP is secreted by intestinal K cells, present glucose in the kidney. As a consequence,
predominantly in the proximal small intestine, glucose excretion increases in the urine,
in response to luminal presence of ingested resulting in glycouria, whereas plasma glucose
fats, carbohydrates and amino acid sources. levels decrease in blood, an insulin
Fat is the most potent stimulator of GIP independent reduction. Thus, SGLT-2
secretion. Intact GIP is a potent stimulator of inhibitors do not confer any risk of
glucose-dependent insulin secretion in healthy hypoglycemia. In addition to improvements in
humans. After secretion, the two N-terminal glycemic control, dapagliflozin therapy is also
amino acids of GIP are cleaved-off by DPP-4 associated with a beneficial reduction in total
and the hormone is then inactivated. It is body weight. A disadvantage for SGLT-2
reported that the GIP works in synergy with inhibitors is an increased incidence of genital
glucose to stimulate β-cell proliferation and infections.
improve survival of pancreatic β-cells . Alpha-glucosidase inhibitors (AGIs): AGIs such
Thiazolidinediones: Thiazolidinediones (TZDs) as acarbose, voglibose and miglitol are pseudo-
including rosiglitazone and pioglitazone are carbohydrates that competitively inhibit α-
drugs acting as insulin sensitizers. The effects glucosidase enzymes located in the brush
of TZDs are mediated through peroxisome border of small intestine that hydrolyze non-
proliferatoractivated receptor-γ (PPAR-γ). absorbable polysaccharides and
PPAR- receptors are mainly located in the oligosaccharides into absorbable
adipocytes, and also distributed in skeletal monosaccharides. As a result, the effect of
muscle, liver and the pancreatic β-cells. The these drugs is to retard glucose absorption
TZD-PPAR complex acts on response elements after a meal, and consequently lowers
in promoter regions to affect the transcription postprandial insulin levels and hyperglycemia
of many genes. They may stimulate production peaks in patients with few β-cell reserves. AGIs
of proteins that increase insulin sensitivity and are commonly used to control postprandial
block transcription of proteins responsible for blood glucose and to reduce the insulin
insulin resistance or inflammation . In addition requirement without causing hypoglycemia
to glucose-lowering effects, pioglitazone may and weight gain. AGIs can be administered as
also improve lipid profiles, possibly due to its monotherapy or in combination with any
partial PPAR-α activity. other blood glucose-lowering drug, including
Pioglitazone has a very low risk of insulin for the treatment of T2DM. The primary
hypoglycemia in monotherapy. It can be taken drawback of α-glucosidase inhibitors is its
by patients with advanced renal insufficiency. gastrointestinal disturbance such as flatulence
Its disadvantages are weight gain, fluid and diarrhea .
retention that can worsen cardiac

Strategies for insulin therapy: Insulin therapy Most T2DM patients are overweight or obese.
was classically considered a last step for T2DM Patients with T2DM and body mass index (BMI)
patients and did not use until all other < 35 kg/m2 are primarily offered conventional
treatments failed. The goals of insulin therapy treatment since there has been considerable
in T2DM are glycemic and metabolic control to debate about extending the benefits of
prevent micro- and macrovascular bariatric surgery to those patients. The
complications. People should be aware if the diabetic patients with BMI > 35 kg/m2 are
insulin dose is too high or incorrectly currently eligible for bariatric surgery,
distributed, hypoglycemia and marked weight according to the NIH Consensus Criteria for
gain may occur. The treatment begins at a dose bariatric surgery. Recent meta-analyses of 16
of 10 to 20 IU of a long-acting insulin studies with 6131 patients and mean 17.3-
preparation. Depending on the patient’s month follow-up have found bariatric surgery
weight, a dose increase by 2 IU every three to be superior to conventional medical therapy
days may be required until the morning in achieving significant weight loss, HbA1c and
glucose values are within the target range. If fasting plasma glucose reduction and diabetes
glycemic peaks after meals are the main remission. Thus, bariatric surgery has been
problem, then insulin therapy would more accepted as the most effective treatment
reasonably be initiated with insulin along with significant metabolic benefits for
administration only at mealtimes. patients with T2DM and BMI > 35 kg/ m2 .
It is increasingly being recognized that insulin Weight loss after surgery is not due to
may be used at an early stage of T2DM. Recent intestinal malabsorption, but due to decreased
treatment guidelines recommend the use of food consumption from decreased appetite.
insulin, especially basal insulin, as part of an Evidence exists that changes in the gut
early treatment regimen in the disease hormonal milieu after gastric bypass can
process. The early insulin therapy may slow or improve insulin resistance immediately after
even halt diabetes progression. In patients surgery and proceed substantial weight loss.
with newly diagnosed T2DM, several small- The exact mechanisms for diabetes emission
scale studies have demonstrated that short remain unknown. There are several
term intensive insulin treatment can induce hypotheses including the hindgut or incretin
disease remission (defined by normal glucose theory, the foregut theory and the midgut or
levels) for up to 2 years. The ADA and EASD intestinal/hepatic regulation theory.
recommend starting insulin treatment with Remission of diabetes is likely to be related to
basal insulin based on both the efficacy and both weight loss and hormonal changes that
relative safety of this approach. Currently occur after surgery.
available basal insulin analogs, such as insulin There were several limitations of this analysis.
glargine (Lantus; Sanofi, Paris, France) and 1). All of these studies were of short durations
insulin detemir (Levemir; Novo Nordisk Inc, and involved a relatively small number of
Plainsboro, NJ) offer better improvement in patients. Obviously, long-term outcomes are
terms of duration of action and reduced peak more important to assess the true impact of
effect. these interventions as they are used to treat
Bariatric surgery: Bariatric surgery includes chronic conditions. 2). A considerable portion
Roux-en-Y gastric bypass (RYGB), laparoscopic of the source data were not run on a
sleeve gastrectomy (LSG), laparoscopic randomized group of patients, but rather a
adjustable gastric banding (LAGB), collection of mainly retrospective reports in
biliopancreatic diversion (BPD) and the the literature. 3). There was a large
biliopancreatic diversion with a duodenal heterogeneity in the definition of diabetes
switch (BPD-DS). The RYGB and the BPD remission in the literature. Remission of T2DM
procedures bypass a full length of normal after bariatric surgery depends on the
intestine (bypass procedures) whereas the definition of the remission used for evaluation.
LAGB and LSG only restrict the normal flow of Chinese herbal medicines: As mentioned
food (restrictive procedures). above, a number of anti-diabetic drugs are

effective for T2DM treatment. However, these Chinese herbal medicines and Western
medications frequently have side effects, such medicine are different. Unlike Western
as weight gain, bone loss, and increased risk of medicine, which usually contains a single
cardiovascular events. These side effects could active ingredient, an herb or herbal concoction
become more prevalent due to continuous may contain several active ingredients relaying
treatment of chronic diseases. Herbal multiple mechanisms and emphasizing a
medications can be a good alternative in regulation of the integrated body system. In
combination with or as a partial replacement addition, as plant drugs, therapeutic effects of
for Western medications. Because herbal herbs are weaker than their Western
medicines are usually derived from natural counterparts in lowering blood glucose levels
plants, they are considered to be relatively safe and their side effects. Because of these
and have fewer side effects compared to the features, Chinese herbs may be more suitable
conventional drugs. Herbal medicine has long for prevention and treatment of early stage
been used in China in the treatment of T2DM and diabetic complications for better
diabetes for several thousands of years and therapeutic outcomes.
currently it has been intensively used for The efficacy and safety of anti-DM herbs are
diabetes treatment. Over 70% of Chinese facing challenges. First, experimental evidence
patients are treated with traditional Chinese regarding active constituents, toxicity,
herbal medicines. Diabetes is a huge burden in pharmacokinetics and efficacy of Chinese
China, where approximately 100 million herbs is deficient. Second, herbal medicines
people have been diagnosed with the disease are not totally free from side effects and most
and the prevalence is 9.7% in China. The of the herbs and herb products on the market
application of herbal medicines for diabetic today have not been subjected to a drug
patients is increasing in clinics across the approval process to verify their safety. These
United States. Investigation shows that among herbs have not been well studied using
people with diabetes, 22.3% of patients use randomized, double-blinded clinical trials,
herbal therapy or folk medicine. It is estimated although many animal studies have been
that more than 200 species of plants exhibit carried out.
hypoglycaemic properties. The investigation Conclusion
shows that about 33 Chinese traditional We describe the current understanding of
medicines such as Radix Astragali seu T2DM diagnostic criteria and antidiabetic
Hedysari, Radix Rehmanniae and Radix medications including Chinese herbs. We
Rehmanniae, Praeparata, Radix Trichosanthis, highlight some issues that should be addressed
are most frequently used in Chinese traditional for clinicians and patients. Although T2DM
prescriptions for the clinical treatment of diagnosis and treatment have been improved
diabetes and its complications. Some Chinese in the past decade, current
anti-diabetic herbs have been proven effective available medicines are not able to completely
although some research findings are not curb the development of T2DM and its
consistent. Clinical evidence and animal tests complications. Thus, it is important to develop
show that many Chinese herbs are beneficial in new drugs with improved safety and efficacy
lowering blood glucose and increase insulin for treatment of T2DM in the future.
sensitivity. Mechanism and philosophy of

Zhao Y, Xu G, Wu W, Yi X (2015) Type 2 Diabetes Mellitus- Disease, Diagnosis and Treatment.
J Diabetes Metab 6:533. doi: 10.4172/2155-6156.1000533