Diabetes Mellitus Type 2

Introduction

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia. It may be due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. According to the International Diabetes Federation (IDF), approximately 415 million adults between the ages of 20 to 79 years had diabetes mellitus in 2015.[1] DM is proving to be a global public health burden as this number is expected to rise to another 200 million by 2040.[1] Chronic hyperglycemia in synergy with the other metabolic aberrations in patients with diabetes mellitus can cause damage to various organ systems, leading to the development of disabling and life-threatening health complications, most prominent of which are microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications leading to a 2-fold to a 4-fold increased risk of cardiovascular diseases. In this review, we provide an overview of the pathogenesis, diagnosis, clinical presentation, and principles of management of diabetes.

Etiology

DM is broadly classified into three types by etiology and clinical presentation, type 1 diabetes, type 2 diabetes, and gestational diabetes (GDM). Some other less common types of diabetes include monogenic diabetes and secondary diabetes.[2][3][4][5]

Type 1 Diabetes Mellitus (T1DM)

Type 1 diabetes mellitus (T1DM) accounts for 5% to 10% of DM and is characterized by autoimmune destruction of insulin-producing beta cells in the islets of the pancreas. As a result, there is an absolute deficiency of insulin. A combination of genetic susceptivity and environmental factors such as viral infection, toxins, or some dietary factors have been implicated as triggers for autoimmunity. T1DM is most commonly seen in children and adolescents though it can develop at any age.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) accounts for around 90% of all cases of diabetes. In T2DM, the response to insulin is diminished, and this is defined as insulin resistance. During this state, insulin is ineffective and is initially countered by an increase in insulin production to maintain glucose homeostasis, but over time, insulin production decreases, resulting in T2DM. T2DM is most commonly seen in persons older than 45 years. Still, it is increasingly seen in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-dense diets.

Gestational Diabetes Mellitus

Hyperglycaemia, which is first detected during pregnancy, is classified as gestational diabetes mellitus (GDM), also known as hyperglycemia in pregnancy. Although it can occur anytime during pregnancy, GDM generally affects pregnant women during the second and third trimesters. According to the American Diabetes Association (ADA), GDM complicates 7% of all pregnancies. Women with GDM and their offspring have an increased risk of developing type 2 diabetes mellitus in the future.

GDM can be complicated by hypertension, preeclampsia, and hydramnios and may also lead to increased operative interventions. The fetus can have increased weight and size (macrosomia) or congenital anomalies. Even after birth, such infants may have respiratory distress syndrome, and subsequent childhood and adolescent obesity. Older age, obesity, excessive gestational weight gain, history of congenital anomalies in previous children, or stillbirth, or a family history of diabetes are risk factors for GDM.

Monogenic Diabetes

A single genetic mutation in an autosomal dominant gene causes this type of diabetes. Examples of monogenic diabetes include conditions like neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY). Around 1% to 5% of all diabetes cases are due to monogenic diabetes. MODY is a familial disorder and usually presents under the age of 25 years.

Secondary Diabetes

Secondary diabetes is caused due to the complication of other diseases affecting pancreas (for example, pancreatitis), hormone disturbances (for example, Cushing’s disease), or due to drugs (for example, corticosteroids).

Epidemiology

Diabetes is a worldwide epidemic. With changing lifestyles and increasing obesity, the prevalence of DM has increased worldwide. The global prevalence of DM was 425 million in 2017. According to the International Diabetes Federation (IDF), in 2015, about 10% of the American population had diabetes. Of these, 7 million were undiagnosed. With an increase in age, the prevalence of DM also increases. About 25% of the population above 65 years of age has diabetes.[5]

Pathophysiology

In T1DM, there is cellular-mediated, autoimmune destruction of pancreatic beta cells. T1DM has a strong genetic predisposition. The major histocompatibility complex (MHC), also known as human leukocyte antigens (HLA), is reported to account for approximately 40% to 50% of the familial aggregation of T1DM. The significant determinants are polymorphisms of class II HLA genes encoding DQ and DR4-DQ8, with DR3-DQ2, found in 90% of T1DM patients.

Another form of T1DM is latent autoimmune diabetes of adults (LADA). It occurs in adulthood, often with a slower course of onset.

The rate of destruction is generally rapid in children and faster in adults. Autoantibodies against islet cells, insulin, glutamic acid decarboxylase-65 (GAD-65), and zinc transporter 8 (Zn T8) may be detected in the serum of such patients. These antibodies wane over time and do not have sufficient diagnostic accuracy to be used routinely for diagnosis, especially after the first year. With the progressive destruction of beta cells, there is little or no secretion of insulin. These patients are generally not obese. They are more prone to develop other autoimmune disorders such as Addison disease, Graves' disease, Hashimoto thyroiditis, celiac disease, among others. A subset of T1DM not associated with insulin autoimmunity and not associated with the above HLA is termed idiopathic T1DM. It is commoner in African and Asians and presents with episodic diabetic ketoacidosis (DKA).

T2DM is an insulin-resistance condition with associated beta-cell dysfunction. Initially, there is a compensatory increase in insulin secretion, which maintains glucose levels in the normal range. As the disease progresses, beta cells change, and the insulin secretion is unable to maintain glucose homeostasis, producing hyperglycemia. Most of the patients with T2DM are obese or have a higher body fat percentage, distributed predominantly in the abdominal region. This adipose tissue itself promotes insulin resistance through various inflammatory mechanisms, including increased FFA release and adipokine dysregulation. Lack of physical activity, prior GDM in those with hypertension, or dyslipidemia also increases the risk of developing T2DM. Evolving data suggest a role for adipokine dysregulation, inflammation, abnormal incretin biology with decreased incretins such as glucagon-like peptide-1 (GLP-I) or incretin resistance, hyperglucagonemia, increased renal glucose reabsorption and abnormalities in gut microbiota.

History and Physical

Patients with diabetes mellitus most commonly present with increased thirst, increased urination, lack of energy and fatigue, bacterial and fungal infections, and delayed wound healing. Some patients can also complain of numbness or tingling in hands or feet or with blurred vision.

These patients can have modest hyperglycemia, which can proceed to severe hyperglycemia or ketoacidosis due to infection or stress. T1DM patients can often present with ketoacidosis (DKA) coma as the first manifestation in about 30% of patients.

Height, weight, and body mass index (BMI) of patients with diabetes mellitus should be recorded. Retinopathy needs to be excluded in such patients by an ophthalmologist. All pulses should be palpated to examine for peripheral arterial disease. Neuropathy should be ruled out by physical examination and history and nephropathy by early morning urine albumin/creatinine ratios of less than 30 mg/g creatinine.

Evaluation

Screening

Persons older than 40 years of age should be screened annually. More frequent screening is recommended for individuals with additional risk factors for diabetes.[6][7][8][9][10]

• Certain races/ethnicities (Native American, African American, Hispanics  or Asian American, Pacific Islander), 
• Overweight or obese persons with a BMI greater than or equal to 25 kg/m2 or 23 kg/m2 in Asian Americans,
• First-degree relative with diabetes mellitus
• History of cardiovascular disease, hypertension
• Low HDL-cholesterol or hypertriglyceridemia, 
• Women with polycystic ovarian syndrome
• Physical inactivity
• Conditions associated with insulin resistance, for example, Acanthosis nigricans.

Women diagnosed with gestational diabetes mellitus (GDM) should have lifelong testing at least every three years. For all other patients, testing should begin at age 45 years, and if results are normal, patients should be tested at a minimum of every 3-years.

The same tests are used to both screen for and diagnose diabetes. These tests also detect individuals with prediabetes.

Diagnosis

Diabetes can be diagnosed either by the hemoglobin A1C criteria or plasma glucose concentration (fasting or 2-hour plasma glucose).

Fasting Plasma Glucose (FPG)

A blood sample is taken after an 8 hour overnight fast. As per ADA, fasting plasma glucose (FPG) level of more than 126 mg/dL (7.0 mm/L) is consistent with the diagnosis.

Two-Hour Oral Glucose Tolerance Test (OGTT)

In this test, the plasma glucose level is measured before and 2 hours after the ingestion of 75 gm of glucose. DM is diagnosed if the plasma glucose (PG) level in the 2-hour sample is more than 200 mg/dL (11.1 mmol/L). It is also a standard test but is inconvenient and more costly than FPG and has major variability issues. Patients need to consume a diet with at least 150 g per day of carbohydrate for 3 to 5 days and not take any medications that can impact glucose tolerance, such as steroids and thiazide diuretics.

Glycated Hemoglobin (Hb) A1C

This test gives an average of blood glucose over the last 2 to 3 months. Patients with an Hb A1C greater than 6.5% (48 mmol/mol) are diagnosed as having DM. Hb A1C is a convenient, rapid, standardized test and shows less variation due to pre-analytical variables. It is not much affected by acute illness or stress.

Hb A1C is costly and has many issues, as discussed below, including lower sensitivity. Hb A1C should be measured using the National Glycohemoglobin Standardization Program (NGSP) certified method standardized to Diabetes Control and Complications Trial (DCCT) assay. It is affected by numerous conditions such as sickle cell disease, pregnancy, hemodialysis, blood loss or transfusion, or erythropoietin therapy. It has not been well validated in non-Caucasian populations.

Anemia due to deficiency of iron or vitamin B12 leads to spurious elevation of Hb A1C, limiting its use in countries with a high prevalence of anemia. Also, in children and the elderly, the relation between Hb A1C and FPG is suboptimal.

For all of the above tests, if the person is asymptomatic, testing should be repeated later to make a diagnosis of diabetes mellitus.

In patients with classic symptoms of hyperglycemia (increased thirst, increased hunger, increased urination), random plasma glucose more than 200 mg/dL is also sufficient to diagnose DM.

FPG, 2-hour PG during 75-g GTT, and Hb A1C are equally appropriate for the diagnosis of DM. There is no concordance between the results of these tests.

Diagnosis of Gestational Diabetes Mellitus

Pregnant women not previously known to have diabetes should be tested for GDM at 24 to 28 weeks of gestation. ADA and American College of Obstetrics and Gynecology (ACOG) recommend using either a 1-step or 2-step approach for diagnosing GDM.

One-Step Strategy

75 gm OGTT is performed after an overnight fast. Blood samples are collected at fasting for 1 hour and 2 hours. GDM is diagnosed if fasting glucose meet or exceed 92 mg/dl (5.1 mmol/l), 1-hour serum glucose of 180 mg/dl (10.0 mmol/l) or 2-hour serum glucose of 153 mg/dl (8.5 mmol/l).

Two-Step Strategy

• Step one: Perform a 50-gram glucose challenge test irrespective of the last meal. If PG at 1-hour after the load is greater than or equal to 140mg/dl (7.8 mmol/l), proceed to step 2.
• Step 2: 100 g glucose OGTT is performed after overnight fasting. Cut off values are fasting PG 95 or 105 mg/dl (5.5/5.8 mmol/l), 1-hour PG of 180 or 190 mg/dl (10.0/10.6 mmol/l), 2-hour PG of 155 or 165 mg/dl (8.6/9.2 mmol/l) or 3-hour PG of 140 or 145 mg/dl (7.8/8.0 mmol/l). GDM is diagnosed if two or more PG levels equal or exceed these cutoffs.

Treatment / Management

For both T1DM and T2DM, the cornerstone of therapy is diet and exercise.[11][12][13]

A diet low in saturated fat, refined carbohydrates, fructose corn syrup, and high in fiber and monounsaturated fats needs to be encouraged. Aerobic exercise for a duration of 90 to 150 minutes per week is also beneficial. The major target in T2DM patients, who are obese, is weight loss.

If adequate glycemia cannot be achieved, metformin is the first-line therapy. Following metformin, many other therapies such as oral sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors. Glucagon-like peptide-1 (GLP-I) receptor agonists, Sodium-glucose co-transporter-2 (SGLT2) inhibitors, pioglitazone, especially if the patient has fatty liver disease, alpha-glucosidase inhibitors, and insulin, are available. Recent studies have shown that the SGLT2 inhibitor, empagliflozin (EMPA), and the GLP-1 receptor agonist, liraglutide, reduce both significant cardiovascular (CV) events and mortality. Hence, in patients with CV disease, these drugs should be considered next. For patients with T1DM, a regime of basal-bolus insulin is the mainstay of therapy. Also, insulin-pump therapy is a reasonable choice. Since hypoglycemia portends increased mortality, preference should be given to therapies that do not induce hypoglycemia, for example, DPP-4 Inhibitors, SGLT-2 inhibitors, GLP-I receptor agonists, and pioglitazone with metformin. The other advantages of SGLT-2 inhibitors and GLP-I receptor agonists are a reduction in body weight, blood pressure (BP), and albuminuria.

To reduce microvascular complications in the majority, the goal Hb A1C should be less than 7%. Also, the BP goal should be less than 130/85 mmHg with a preference for angiotensin-converting enzyme (ACE)/angiotensin receptor blocker (ARB) therapy. Fundal exams should be undertaken as proposed by guidelines and urine albumin excretion at least twice a year.

For the lipid panel, the goal should be an LDL-C less than 100 mg/dl if no atherosclerotic cardiovascular disease (ASCVD) or less than 70 mg/dl if ASCVD present. The drug of choice is a statin since these drugs reduce CV events and CV mortality. Consider adding ezetimibe and PCSK9 inhibitors for patients with ASCVD who are not at goal.

Since the different complications and therapies have been detailed in other Statpearls review articles, we have outlined only the principles of therapy.[14][15]

Differential Diagnosis

The list of differential diagnosis of diabetes mellitus consists of various conditions that would exhibit similar signs and symptoms [16][17]:

• Drug-induced signs and symptoms due to corticosteroids, neuroleptics, pentamidine, etc
• Genetic aberrations in beta-cell function and insulin action
• Metabolic syndrome (syndrome X)[18]
• Infection
• Endocrinopathies such as acromegaly, Cushing disease, pheochromocytoma, hypothyroidism, etc[19]
• Complications of iron overload (hemochromatosis)
• Conditions affecting the exocrine part of the pancreas such as pancreatitis, cystic fibrosis, etc[20]

Prognosis

DM is associated with increased ASCVD, and treating BP, statin use, regular exercise, and smoking cessation are of great importance in ameliorating risk. The overall excess mortality in those with T2DM is around 15% higher but varies widely. The prevalence of vision-threatening diabetic retinopathy in the United States is about 4.4% among adults with diabetes, while it is 1% for end-stage renal disease. Today, with pharmacotherapy for hyperglycemia, as well as lowering LDL cholesterol and managing BP with ACE/ARB therapy, with other antihypertensive medications and aspirin in secondary prevention, vascular complications can be managed adequately resulting in a reduction in morbidity and mortality.[21][22]

Complications

Persistent hyperglycemia in uncontrolled diabetes mellitus can cause several complications, both acute and chronic. Diabetes mellitus is one of the leading causes of cardiovascular disease (CVD), blindness, kidney failure, and amputation of lower limbs. Acute complications include hypoglycemia, diabetic ketoacidosis, hyperglycemic hyperosmolar state, and hyperglycaemic diabetic coma. Chronic microvascular complications are nephropathy, neuropathy, and retinopathy, whereas chronic macrovascular complications are coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease. It is estimated that every year 1.4% to 4.7% of middle-aged people with diabetes have a CVD event.[23][24]

Deterrence and Patient Education

Patients must be educated about the importance of blood glucose management to avoid complications associated with DM. Stress must be given on lifestyle management, including diet control and physical exercise. Self-monitoring of blood glucose is an important means for patients taking responsibility for their diabetes management. Regular estimation of glucose, glycated hemoglobin, and lipid levels is necessary.

Healthcare professionals should educate patients about the symptoms of hypoglycemia (such as tachycardia, sweating, confusion) and required action (ingestion of 15 to 20 gm of carbohydrate).

Patients should be motivated to stop smoking. Emphasis is required on regular eye check-ups and foot care.

Pearls and Other Issues

• T1DM is characterized by autoimmune destruction of pancreatic beta cells in the majority.
• T2DM is caused due to duel defects in insulin resistance and insulin secretion.
• Gestational diabetes is associated with maternal as well as fetal complications.
• Exercise and a healthy diet are beneficial in both type 1 and type 2 diabetes mellitus.
• Novel therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors are safer since they do not cause hypoglycemia, are weight neutral or result in weight loss and BP and impact vascular complications favorably.

Enhancing Healthcare Team Outcomes

The diagnosis and management of type 2 diabetes mellitus are with an interprofessional team. These patients need an appropriate referral to the ophthalmologist, nephrologist, cardiologist, and vascular surgeon. Also, patients need to be educated about lifestyle changes that can help lower blood glucose. All obese patients should be encouraged to lose weight, exercise, and eat a healthy diet. The primary care provider and diabetic nurse must encourage all diabetics top smoking and abstain from drinking alcohol. The complications of diabetes mellitus are limb and life-threatening and seriously diminish the quality of life.[25][26][27]

Continuing Education / Review Questions

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