• Sign Up

Use coupon code BLACKFRIDAY2020 at checkout for 30% off now through Monday!

Diabetes Mellitus


Diabetes Mellitus

Article Author:
Amit Sapra
Article Editor:
Priyanka Bhandari
Updated:
11/19/2020 6:46:14 PM
For CME on this topic:
Diabetes Mellitus CME
PubMed Link:
Diabetes Mellitus

Introduction

Diabetes mellitus is taken from the Greek word Diabetes, meaning siphon - to pass through and the Latin word mellitus meaning sweet. A review of the history shows that the term "diabetes" was first used by Apollonius of Memphis around 250 to 300 BC. Ancient Greek, Indian, Egyptian civilizations discovered the sweet nature of urine in this condition, and hence the propagation of the word Diabetes Mellitus came into being. Mering and Minkowski, in 1889, discovered the role of the pancreas in the pathogenesis of Diabetes. In 1922 Banting, Best, and Collip purified the hormone insulin from the pancreas of cows at the University of Toronto, leading to the availability of an effective treatment for Diabetes in 1922. Over the years, exceptional work has taken place, and multiple discoveries, as well as management strategies, have been created to tackle this growing problem. Unfortunately, even today, diabetes is one of the most common chronic diseases in the country and worldwide. In the US, it remains as the seventh leading cause of death.

Diabetes Mellitus (DM) is a metabolic disease, involving inappropriately elevated blood glucose levels. DM has several categories, including type 1, type 2, maturity-onset diabetes of the young (MODY), gestational diabetes, neonatal diabetes, and secondary causes due to endocrinopathies, steroid use, etc. The main subtypes of DM are Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM), which classically result from defective insulin secretion (T1DM) and/or action (T2DM). T1DM presents in children or adolescents, while T2DM is thought to affect middle-aged and older adults who have prolonged hyperglycemia due to poor lifestyle and dietary choices. The pathogenesis for T1DM and T2DM is drastically different, and therefore each type has various etiologies, presentations, and treatments.

Etiology

In the islets of Langerhans in the pancreas, there are two main subclasses of endocrine cells: insulin-producing beta cells and glucagon secreting alpha cells. Beta and alpha cells are continually changing their levels of hormone secretions based on the glucose environment. Without the balance between insulin and glucagon, the glucose levels become inappropriately skewed. In the case of DM, insulin is either absent and/or has impaired action (insulin resistance), and thus leading to hyperglycemia.

T1DM is characterized by the destruction of beta cells in the pancreas, typically secondary to the autoimmune destruction of beta cells. The result is the absolute destruction of beta cells, and consequentially, insulin is absent or extremely low.

T2DM involves a more insidious onset where an imbalance between insulin levels and insulin sensitivity causes a functional deficit of insulin. Insulin resistance is multifactorial but commonly develops from obesity and aging.

The genetic background for both types is critical as a risk factor. As the human genome gets further explored, there are different loci found that confer risk for DM. Polymorphisms have been known to influence the risk for T1DM, including major histocompatibility complex (MHC) and human leukocyte antigen (HLA).[1]

T2DM involves a more complex interplay between genetics and lifestyle. There is clear evidence suggesting that T2DM is has a stronger hereditary profile as compared to T1DM. The majority of patients with the disease have at least one parent with T2DM.[2]

Monozygotic twins with one affected twin have a 90% likelihood of the other twin developing T2DM in his/her lifetime.[3] Approximately 50 polymorphisms to date have been described to contribute to the risk or protection for T2DM. These genes encode for proteins involved in various pathways leading to DM, including pancreatic development, insulin synthesis, secretion, and development, amyloid deposition in beta cells, insulin resistance, and impaired gluconeogenesis regulation. A genome-wide association study (GWAS) found genetic loci for transcription factor 7-like 2 gene (TCF7L2), which increases the risk for T2DM.[4][5] Other loci that have implications in the development of T2DM include NOTCH2, JAZF1, KCNQ1, and WFS1.[6][7]

MODY is a heterogeneous disorder identified by non-insulin dependent diabetes diagnosed at a young age (usually under 25 years). It carries an autosomal dominant transmission and does not involve autoantibodies as in T1DM. Several genes have implications in this disease, including mutations to hepatocyte nuclear factor-1-alpha (HNF1A) and the glucokinase (GCK) gene, which occurs in 52 to 65 and 15 to 32 percent of MODY cases, respectively.[8][9] The genetics of this disease are still unclear as some patients have mutations but never develop the disease, and others will develop clinical symptoms of MODY but have no identifiable mutation.

Gestational diabetes is essentially diabetes that manifests during pregnancy. It is still unknown why it develops; however, some speculate that HLA antigens may play a role, specifically HLA DR2, 3, and 4. Excessive proinsulin is also thought to play a role in gestational diabetes, and some suggest that proinsulin may induce beta-cell stress. Others believe that high concentrations of hormones such as progesterone, cortisol, prolactin, human placental lactogen, and estrogen may affect beta-cell function and peripheral insulin sensitivity.[10]

Several endocrinopathies, including acromegaly, Cushing syndrome, glucagonoma, hyperthyroidism, hyperaldosteronism, and somatostatinomas, have been associated with glucose intolerance and diabetes mellitus, due to the inherent glucogenic action of the endogenous hormones excessively secreted in these conditions. Conditions like idiopathic hemochromatosis are associated with diabetes mellitus due to excessive iron deposition in the pancreas and the destruction of the beta cells.

Epidemiology

Globally, 1 in 11 adults has DM (90% having T2DM). The onset of T1DM gradually increases from birth and peaks at ages 4 to 6 years and then again from 10 to 14 years.[11] Approximately 45% of children present before age ten years.[12] The prevalence in people under age 20 is about 2.3 per 1000. While most autoimmune diseases are more common in females, there are no apparent gender differences in the incidence of childhood T1DM. In some populations, such as in older males of European origin (over 13 years), they may be more likely to develop T1DM compared to females (3:2 male to female ratio).[13] The incidence of T1DM has been increasing worldwide. In Europe, Australia, and the Middle East, rates are rising by 2 to 5% annually.[14][15][16] In the United States, T1DM rates rose in most age and ethnic groups by about 2% yearly, and rates are higher in Hispanic youth.[17] The exact reason for this pattern remains unknown. However, some metrics, such as the United States Military Health System data repository, found plateauing over 2007 to 2012 with a prevalence of 1.5 per 1000 and incidence of 20.7 to 21.3 per 1000.[18]

The onset of T2DM is usually later in life, though obesity in adolescents has led to an increase in T2DM in younger populations. T2DM has a prevalence of about 9% in the total population of the United States, but approximately 25% in those over 65 years. The International Diabetes Federation estimates that 1 in 11 adults between 20 and 79 years had DM globally in 2015. Experts expect the prevalence of DM to increase from 415 to 642 million by 2040, with the most significant increase in populations transitioning from low to middle-income levels.[19] T2DM varies among ethnic groups and is 2 to 6times more prevalent in African Americans, Native Americans, Pima Indians, and Hispanic Americans compared to Whites in the United States.[20][21] While ethnicity alone plays a vital role in T2DM, environmental factors also greatly confer risk for the disease. For example, Pima Indians in Mexico are less likely to develop T2DM compared to Pima Indians in the United States (6.9 vs. 38%).[22]

Pathophysiology

A patient with DM has the potential for hyperglycemia. The pathology of DM can be unclear since several factors can often contribute to the disease. Hyperglycemia alone can impair pancreatic beta-cell function and contributes to impaired insulin secretion. Consequentially, there is a vicious cycle of hyperglycemia leading to the impaired metabolic state. Blood glucose levels above 180 mg/dL are often considered hyperglycemic in this context, though because of the variety of mechanisms, there is no clear cutoff point. Patients experience osmotic diuresis due to saturation of the glucose transporters in the nephron at higher blood glucose levels. Although the effect is variable, serum glucose levels above 250 mg/dL are likely to cause symptoms of polyuria and polydipsia.

Insulin resistance is attributable to excess fatty acids and proinflammatory cytokines, which leads to impaired glucose transport and increases fat breakdown. Since there is an inadequate response or production of insulin, the body responds by inappropriately increasing glucagon, thus further contributing to hyperglycemia. While insulin resistance is a component of T2DM, the full extent of the disease results when the patient has inadequate production of insulin to compensate for their insulin resistance. 

Chronic hyperglycemia also causes nonenzymatic glycation of proteins and lipids. The extent of this is measurable via the glycation hemoglobin (HbA1c) test. Glycation leads to damage in small blood vessels in the retina, kidney, and peripheral nerves. Higher glucose levels hasten the process. This damage leads to the classic diabetic complications of diabetic retinopathy, nephropathy, and neuropathy and the preventable outcomes of blindness, dialysis, and amputation, respectively.[23]

History and Physical

During patient history, questions about family history, autoimmune diseases, and insulin-resistant are critical to making the diagnosis of DM. It often presents asymptomatically, but when symptoms develop, patients usually present with polyuria, polydipsia, and weight loss. On physical examination of someone with hyperglycemia, one may see poor skin turgor (from dehydration) and smell a distinctive fruity odor on their breath (in patients with ketosis). In the setting of diabetic ketoacidosis (DKA), clinicians may note Kussmaul respirations, fatigue, nausea, and vomiting. Funduscopic examination in a DM patient may show hemorrhages or exudates on the macula. In frank diabetic retinopathy, retinal venules may appear dilated or occluded. The proliferation of new blood vessels is also a concern for Ophthalmologists and can hasten retinal hemorrhages and macular edema, ultimately resulting in blindness.
 
While T1DM and T2DM can present similarly, they can be distinguished based on clinical history and examination. T2DM patients are typically overweight/obese and present with signs of insulin resistance, including acanthosis nigricans, which are hyperpigmented, velvety patches on the skin of the neck, axillary, or inguinal folds. Patients with a longer course of hyperglycemia may have blurry vision, frequent yeast infections, numbness, or neuropathic pain. The clinicians must ask the patient bout any recent skin changes in their feet during each visit. The diabetic foot exam, including the monofilament test, should be a part of the routine physical exam.

Evaluation

The diagnosis of T1DM is usually through a characteristic history supported by elevated serum glucose levels (fasting glucose greater than 126 mg/dL, random glucose over 200 mg/dL, or hemoglobin A1C (HbA1c exceeding 6.5%) with or without antibodies to glutamic acid decarboxylase (GAD) and insulin.

Fasting glucose levels and HbA1c testing are useful for the early identification of T2DM. If borderline, a glucose tolerance test is an option to evaluate both fasting glucose levels and serum response to an oral glucose tolerance test (OGTT). Prediabetes, which often precedes T2DM, presents with a fasting blood glucose level of 100 to 125 mg/dL or a 2-hour post-oral glucose tolerance test (post-OGTT) glucose level of 140 to 200 mg/dL.[24][25]

According to the American Diabetes Association (ADA), a diagnosis of diabetes is through any of the following (24): An HbA1c level of 6.5% or higher; A fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or higher (no caloric intake for at least 8 hours); A two-hour plasma glucose level of 11.1 mmol/L or 200 mg/dL or higher during a 75-g OGTT; A random plasma glucose of 11.1 mmol/L or 200 mg/dL or higher in a patient with symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis. The ADA recommends screening adults aged 45 years and older regardless of risk, while the United States Preventative Service Task Force suggests screening individuals between 40 to 70 years who are overweight.[26].

To test for gestational diabetes, all pregnant patients have screening between 24 to 28 weeks of gestation with a 1-hour fasting glucose challenge test. If blood glucose levels are over 140mg/dL, patients have a 3-hour fasting glucose challenge test to confirm a diagnosis. A positive 3-hours OGTT test is when there is at least one abnormal value (greater than or equal to 180, 155, and 140 mg/dL for fasting one-hour, two-hour, and 3-hour plasma glucose concentration, respectively).[27]

Several lab tests are useful in the management of chronic DM. Home glucose testing can show trends of hyper- and hypoglycemia. The HbA1c test indicates the extent of glycation due to hyperglycemia over three months (the life of the red blood cell). Urine albumin testing can identify the early stages of diabetic nephropathy. Since patients with diabetes are also prone to cardiovascular disease, serum lipid monitoring is advisable at the time of diagnosis. Similarly, some recommend monitoring thyroid status by obtaining a blood level of thyroid-stimulating hormone annually due to a higher incidence of hypothyroidism.[24][25] 

Treatment / Management

The physiology and treatment of diabetes are complex and require a multitude of interventions for successful disease management. Diabetic education and patient engagement are critical in management. Patients have better outcomes if they can manage their diet (carbohydrate and overall caloric restriction), exercise regularly (more than 150 minutes weekly), and independently monitor glucose.[28] Lifelong treatment is often necessary to prevent unwanted complications. Ideally, glucose levels should be maintained at 90 to 130 mg/dL and HbA1c at less than 7%. While glucose control is critical, excessively aggressive management may lead to hypoglycemia, which can have adverse or fatal outcomes.

Since T1DM is a disease primarily due to the absence of insulin, insulin administration through daily injections, or an insulin pump, is the mainstay of treatment. In T2DM, diet and exercise may be adequate treatments, especially initially. Other therapies may target insulin sensitivity or increase insulin secretion by the pancreas. The specific subclasses for drugs include biguanides (metformin), sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, glucagonlike-peptide-1 agonist, dipeptidyl peptidase IV inhibitors (DPP-4), selective, amylinomimetics, and sodium-glucose transporter-2 (SGLT-2) inhibitors. Metformin is the first line of the prescribed diabetic medications and works by lowering basal and postprandial plasma glucose. Insulin administration may also be necessary for T2DM patients, especially those with inadequate glucose management in the advanced stages of the disease. In morbidly obese patients, bariatric surgery is a possible means to normalize glucose levels. It is recommended for individuals who have been unresponsive to other treatments and who have significant comorbidities.[29] The GLP-1 agonists liraglutide and semaglutide correlate with improved cardiovascular outcomes. The SGLT-2 inhibitors empagliflozin and canagliflozin have also shown to improve cardiovascular outcomes along with potential renoprotection as well as prevention for the development of heart failure.

Regular screenings are necessary since microvascular complications are a feared complication of diabetes. Regular diabetic retinal exams should be performed by qualified medical personnel to assess for diabetic retinopathy. Neurologic examination with monofilament testing can identify patients with neuropathy at risk for amputation. Clinicians can also recommend patients perform daily foot inspections to identify foot lesions that may go unnoticed due to neuropathy. Low-dose tricyclic antidepressants, duloxetine, anticonvulsants, topical capsaicin, and pain medications may be necessary to manage neuropathic pain in diabetes. Urine microalbumin testing can also assess for early renal changes from diabetes with albuminuria greater than 30mg/g creatinine along with the estimated GFR. The antiproteinuric effect of the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs)  makes them the preferred agents to delay the progression from microalbuminuria to macroalbuminuria in patients with both Type 1 or Type 2 diabetes mellitus.

FDA has approved pregabalin and duloxetine for the treatment of diabetic peripheral neuropathy. Tricyclic antidepressants and anticonvulsants have also seen use in the management of the pain of diabetic neuropathy with variable success. 

The ADA also recommends regular blood pressure screening for diabetics, with the goal being 130 mmHg systolic blood pressure and 85 mmHg diastolic blood pressure.[30] Pharmacologic therapy for hypertensive diabetics typically involves angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, beta-blockers, and/or calcium channel blockers. The ADA recommends lipid monitoring for diabetics with a goal of low-density lipoprotein cholesterol (LDL-C) being less than 100 mg/dL if no CVD and less than 70 mg/dl if ASCVD is present. Statins are the first-line treatment for the management of dyslipidemia in diabetics. The ADA suggests that low dose aspirin may also be beneficial for diabetic patients who are at high risk for cardiovascular events [31]; however, the role of aspirin in reducing cardiovascular events in diabetic remains unclear.[32][33]

Differential Diagnosis

In addition to T1DM, T2DM, and MODY, any disorder that damages the pancreas can result in DM. Several diseases of the exocrine pancreas, including:[34] 

  • Cystic fibrosis
  • Hereditary hemochromatosis
  • Pancreatic cancer
  • Chronic pancreatitis

Hormonal syndromes that can lead to impaired insulin secretion include:

  • Pheochromocytoma
  • Acromegaly
  • Cushing syndrome

Drug-induced insulin resistance is also in the differential of classical diabetes. These drugs include:

  • Phenytoin
  • Glucocorticoids
  • Estrogen

Other diseases in the differential of diabetes mellitus include:

  • Gestational diabetes[10]
  • Thyroid disorders

Pertinent Studies and Ongoing Trials

Various trials have been undertaken to understand the cardiovascular outcomes with antidiabetic medications. The LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), was a double-blinded trial comparing the use of liraglutide, which is a GLP -1 agonist to placebo in around 10000 patients. After a follow-up period of about four years, liraglutide was shown to reduce mortality from cardiovascular causes as well as all-cause mortality. It also seemed to reduce the first occurrence of the first nonfatal MI and stroke.

The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) have shown considerable reductions in mortality and heart failure hospitalization risks in patients with type 2 diabetes mellitus (T2D), by and cardiovascular disease with empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

The CANVAS trial (Canagliflozin Cardiovascular Assessment Study) subsequently reported a reduction in 3-point major adverse cardiovascular events and heart failure hospitalization risk. The proposed mechanism through which SGLT2 inhibitors work helps patients with heart failure is via the promotion of natriuresis and osmotic diuresis and reduced preload. SGLT2 inhibition is also associated with the preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients who have HF with and without T2 diabetes mellitus.

Toxicity and Side Effect Management

One of the most common adverse effects of insulin is hypoglycemia. Gastrointestinal upset is the most common side effect of most of the T2DM medications. Metformin can lead to lactic acidosis and should be used with caution in patients with renal disease and discontinued if the estimated glomerular filtration rate (e-GFR) is under 30 mL/min. Sulfonylureas can lead to hypoglycemia and may promote cardiovascular death in diabetic patients.[35] Thiazolidinediones have fallen out of favor in clinical practice due to its adverse effects, specifically resulting in fluid retention, worsening heart failure, and fractures.[36][37] DPP-4 may increase the risk for upper respiratory tract infections but may have less nausea and diarrhea compared to other drugs such as metformin.[38][39] SGLT-2 inhibitors can lead to increased urinary tract infections due to increased urinary glucose excretion.[40] Both SGLT2 inhibitors and GLP-1 Receptor agonists reduce ASCVD Events and are now considered the second line to metformin in such patients. 

Prognosis

Diabetes mellitus was the seventh leading cause of death in the United States in 2015.[41] The prognosis of DM gets significantly influenced by the degree of glucose management. Chronic hyperglycemia significantly increases the risk of DM complications. The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study found that individuals with T1DM and T2DM respectively had increased microvascular complications with chronic hyperglycemia.[42][43] Patients who can revert to normal glucose during the progression from pre-diabetes to frank DM had a good prognosis and may be able to slow disease progression.[44]

Complications

Regardless of the specific type of diabetes, complications involve microvascular, macrovascular, and neuropathic issues. Microvascular and macrovascular complications vary according to the degree and the duration of poorly control diabetes and include nephropathy, retinopathy, neuropathy, and ASCVD events, especially if it is associated with other comorbidities like dyslipidemia and hypertension.[45] One of the most devastating consequences of DM is its effect on cardiovascular disease (ASCVD). Approximately two-thirds of those with DM will die from a myocardial infarction or stroke.[46] In T2DM, fasting glucose of more than 100 mg/dL significantly contributes to the risk of ASCVD, and cardiovascular risk can develop before frank hyperglycemia.[47][48]

DM is also a common cause of blindness in adults aged 20 to 74 years in the United States. Diabetic retinopathy contributes to 12000 to 24000 new cases of blindness annually, and treatments generally consist of laser surgery and glucose control.[49]

Renal disease is another significant cause of morbidity and mortality in DM patients. It is the leading contributor to end-stage renal disease (ESRD) in the United States, and many patients with ESRD with the need to start dialysis or receive a kidney transplant [49]. If the albuminuria seems to persist in the range of 30 to 300 mg/day(microalbuminuria), it seems to be a predictable earliest marker for the onset of diabetic neuropathy. Once macroalbuminuria (greater than 300 mg/24 hr) sets in, the progression to ESRD  seems to hasten up. The random spot urine specimen for measurement of the albumin-to-creatinine ratio seems to be a quick, easy, predictable, and preferred method is the most widely used and preferred method to detect microalbuminuria. Two of three tests, done over a six month showing a persistent level greater than 30 mcg/mg creatinine, confirms the diagnosis of microalbuminuria.

DM is also the leading cause of limb amputations in the United States; this is primarily due to vasculopathy and neuropathy associated with DM.[49] Many patients who develop neuropathy need to have regular foot exams to prevent infection from wounds that go unnoticed.

The duration of diabetes is the most crucial risk factor for the development of Diabetic Retinopathy. In people with type 1 diabetes typically sets in about t 5 years after disease onset. Hence it is recommended to start the yearly retinal exams in these patients about five years after diagnosis. Among patients with type 2 diabetes, many patients might already have retinal changes at the time of diagnosis. Approximately 10%  at ten years, 40% at 15 years, and 60% at 20 years will have nonproliferative retinal disease. In these patients, the recommendation is to start the yearly retinal screening at the time of diagnosis. Study after study has shown that reasonable glycemic control favorably affected the onset and progression of diabetic retinopathy. Uncontrolled blood pressure is an added risk factor for macular edema. Lowering the blood pressure in the diabetic patient thus also affects the risk of progression of the retinopathy. Injection of antibodies vascular endothelial growth factor (anti-VEGF) agents are generally in use as the initial therapy in cases of macular edema. In cases of nonproliferative diabetic retinopathy, pan-retinal photocoagulation is being used. In cases of diabetic proliferative retinopathy, combined modalities of anti-VEGF agents and pan-retinal photocoagulation are now in use.
Sudden loss of vision can occur for several reasons in patients with diabetes mellitus, the most common being vitreous hemorrhage. Less common causes that merit consideration include vascular occlusion (central retinal vein or branch vein occlusion involving the macula), retinal detachment, end-stage glaucoma, and ischemic optic neuropathy.

Furthermore, evidence suggests that T2DM may also contribute to cancer development, specifically bladder cancer, in those using pioglitazone.[50] Patients using metformin had improved cancer-specific survival in those with prostate, pancreatic, breast, and colorectal cancers. However, it is unclear how metformin plays a role in modulating cancer in diabetic patients.[51]

Those with gestational diabetes are at a higher risk for cesarean delivery and chronic hypertension. T2DM pregnant patients generally have a better prognosis in terms of neonatal and pregnancy complications compared to those with T2DM. Generally, neonates of DM mothers will present with hypoglycemia and macrosomia.[52]

The most acute complication of DM is DKA, which typically presents in T1DM. This condition is usually either due to inadequate dosing, missed doses, or ongoing infection.[53] In this condition, the lack of insulin means that tissues are unable to obtain glucose from the bloodstream. Compensation for this causes the metabolism of lipids into ketones as a substitute energy source, which causes systemic acidosis, and can be calculated as a high anion-gap metabolic acidosis. The combination of hyperglycemia and ketosis causes diuresis, acidemia, and vomiting leading to dehydration and electrolyte abnormalities, which can be life-threatening. In T2DM, hyperosmolar hyperglycemic syndrome (HHS) is an emergent concern. It presents similarly to DKA with excessive thirst, elevated blood glucose, dry mouth, polyuria, tachypnea, and tachycardia. However, unlike DKA, HHS typically does not present with excessive urinary ketones since insulin still gets produced by pancreatic beta cells. Treatment for DKA or HHS involves insulin administration and aggressive intravenous hydration. Careful management of electrolytes, particularly potassium, is critical in the management of these emergent conditions.[54]

Deterrence and Patient Education

Healthcare professionals should take an active approach to educate patients with DM. It is misguided for patients to think that lifestyle changes for a limited time are appropriate, and instead, lifelong lifestyle changes may be necessary to control their DM adequately. A randomized, controlled trial identified that individualized education is more effective compared to group education in patients who had poorly controlled DM.[55] Often, non-physician healthcare professionals (e.g., nurses, pharmacists) have extensive training in DM education and have more time for individualized education.

Pearls and Other Issues

Amino acid metabolism may play a critical role in the development of T2DM. Studies have shown that there is a 4-fold increase in isoleucine, phenylalanine, and tyrosine in individuals with hyperglycemia. Researchers found that these amino acids were elevated up to 12 years before the onset of the disease.[56] Recent studies have further elucidated the role of these metabolites in the development, screening, and treatment of metabolic syndrome (MetS), a cardiometabolic cluster that predisposes patients to T2DM and CVD. Studies have shown that choline, L-carnitine, and trimethylamine-N-oxide were associated with inflammatory pathways and increased the risk of metabolic dysfunction in nascent MetS patients, who meet classification for MetS but do not have T2DM and cardiovascular disease.[57] Literature has also shown increased levels of isoleucine and tyrosine and decreased levels of lysine and methionine. These metabolites appear to be early biomarkers of nascent MetS and significant contributors to the pro-inflammatory burden of MetS.

Low levels of lysine, in particular, were associated with increased inflammation and elevated blood glucose. Thus, increased dietary lysine may promote anti-inflammatory effects.[58] In a recent investigation, researchers found phosphatidylcholine 34:2, PC (34:2), GABA, and d-pyroglutamic acid (PGA) were significantly increased in nascent MetS and correlated positively with certain inflammatory parameters.[59][60] These findings further support the role of metabolites in the early development of T2DM and suggest that they may have a role in the pro-inflammatory state associated with diabetes.

Enhancing Healthcare Team Outcomes

Primary care clinicians are often the first to identify diabetes in their patients. Since DM is a complex disease, it requires an interprofessional team approach to management. Nurse practitioners and physician assistants can be critical to ensuring proper patient follow-ups and monitoring the efficacy of treatments. Nutritionists and diabetes educators can also provide consultations to help educate patients on appropriate lifestyle modifications and at home glucose management.

Ophthalmologists, neurologists, podiatrists, and nephrologists may also be part of the healthcare team to ensure that patients with DM have adequate screenings to prevent devastating microvascular complications. Endocrinologists may be consulted when patients have a complex presentation or are unresponsive to initial treatments. Of course, pharmacists play a crucial role in evaluating proper medication administration and preventing polypharmacy in DM patients who are often taking multiple medications for the frank disease and its complications; they can ensure optimal dosing and recommend the most efficient regimens to achieve glycemic control, and also educate the patient on the medications and disease process.

Sperl-Hillen et al. found that patients with suboptimally controlled diabetes had better glucose control outcomes when given individualized education compared to group education. These patients also had better psychosocial and behavioral outcomes.[55] Consequentially this emphasizes the role of an interprofessional team approach, including physicians, specialists, specialty trained diabetic nurses educators, and pharmacists who are conversing across disciplines to optimize patient-specific management leading to improved outcomes [Level 5]


References

[1] Rajaei E,Jalali MT,Shahrabi S,Asnafi AA,Pezeshki SMS, HLAs in Autoimmune Diseases: Dependable Diagnostic Biomarkers? Current rheumatology reviews. 2019 Jan 15;     [PubMed PMID: 30644346]
[2] Klein BE,Klein R,Moss SE,Cruickshanks KJ, Parental history of diabetes in a population-based study. Diabetes care. 1996 Aug;     [PubMed PMID: 8842599]
[3] Barnett AH,Eff C,Leslie RD,Pyke DA, Diabetes in identical twins. A study of 200 pairs. Diabetologia. 1981 Feb;     [PubMed PMID: 7193616]
[4] Saxena R,Voight BF,Lyssenko V,Burtt NP,de Bakker PI,Chen H,Roix JJ,Kathiresan S,Hirschhorn JN,Daly MJ,Hughes TE,Groop L,Altshuler D,Almgren P,Florez JC,Meyer J,Ardlie K,Bengtsson Boström K,Isomaa B,Lettre G,Lindblad U,Lyon HN,Melander O,Newton-Cheh C,Nilsson P,Orho-Melander M,Råstam L,Speliotes EK,Taskinen MR,Tuomi T,Guiducci C,Berglund A,Carlson J,Gianniny L,Hackett R,Hall L,Holmkvist J,Laurila E,Sjögren M,Sterner M,Surti A,Svensson M,Svensson M,Tewhey R,Blumenstiel B,Parkin M,Defelice M,Barry R,Brodeur W,Camarata J,Chia N,Fava M,Gibbons J,Handsaker B,Healy C,Nguyen K,Gates C,Sougnez C,Gage D,Nizzari M,Gabriel SB,Chirn GW,Ma Q,Parikh H,Richardson D,Ricke D,Purcell S, Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, N.Y.). 2007 Jun 1;     [PubMed PMID: 17463246]
[5] Sladek R,Rocheleau G,Rung J,Dina C,Shen L,Serre D,Boutin P,Vincent D,Belisle A,Hadjadj S,Balkau B,Heude B,Charpentier G,Hudson TJ,Montpetit A,Pshezhetsky AV,Prentki M,Posner BI,Balding DJ,Meyre D,Polychronakos C,Froguel P, A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007 Feb 22;     [PubMed PMID: 17293876]
[6] Yasuda K,Miyake K,Horikawa Y,Hara K,Osawa H,Furuta H,Hirota Y,Mori H,Jonsson A,Sato Y,Yamagata K,Hinokio Y,Wang HY,Tanahashi T,Nakamura N,Oka Y,Iwasaki N,Iwamoto Y,Yamada Y,Seino Y,Maegawa H,Kashiwagi A,Takeda J,Maeda E,Shin HD,Cho YM,Park KS,Lee HK,Ng MC,Ma RC,So WY,Chan JC,Lyssenko V,Tuomi T,Nilsson P,Groop L,Kamatani N,Sekine A,Nakamura Y,Yamamoto K,Yoshida T,Tokunaga K,Itakura M,Makino H,Nanjo K,Kadowaki T,Kasuga M, Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nature genetics. 2008 Sep;     [PubMed PMID: 18711367]
[7] Zeggini E,Scott LJ,Saxena R,Voight BF,Marchini JL,Hu T,de Bakker PI,Abecasis GR,Almgren P,Andersen G,Ardlie K,Boström KB,Bergman RN,Bonnycastle LL,Borch-Johnsen K,Burtt NP,Chen H,Chines PS,Daly MJ,Deodhar P,Ding CJ,Doney AS,Duren WL,Elliott KS,Erdos MR,Frayling TM,Freathy RM,Gianniny L,Grallert H,Grarup N,Groves CJ,Guiducci C,Hansen T,Herder C,Hitman GA,Hughes TE,Isomaa B,Jackson AU,Jørgensen T,Kong A,Kubalanza K,Kuruvilla FG,Kuusisto J,Langenberg C,Lango H,Lauritzen T,Li Y,Lindgren CM,Lyssenko V,Marvelle AF,Meisinger C,Midthjell K,Mohlke KL,Morken MA,Morris AD,Narisu N,Nilsson P,Owen KR,Palmer CN,Payne F,Perry JR,Pettersen E,Platou C,Prokopenko I,Qi L,Qin L,Rayner NW,Rees M,Roix JJ,Sandbaek A,Shields B,Sjögren M,Steinthorsdottir V,Stringham HM,Swift AJ,Thorleifsson G,Thorsteinsdottir U,Timpson NJ,Tuomi T,Tuomilehto J,Walker M,Watanabe RM,Weedon MN,Willer CJ,Illig T,Hveem K,Hu FB,Laakso M,Stefansson K,Pedersen O,Wareham NJ,Barroso I,Hattersley AT,Collins FS,Groop L,McCarthy MI,Boehnke M,Altshuler D, Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nature genetics. 2008 May;     [PubMed PMID: 18372903]
[8] Fajans SS,Bell GI,Polonsky KS, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. The New England journal of medicine. 2001 Sep 27;     [PubMed PMID: 11575290]
[9] Shields BM,Hicks S,Shepherd MH,Colclough K,Hattersley AT,Ellard S, Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010 Dec;     [PubMed PMID: 20499044]
[10] Kühl C, Etiology and pathogenesis of gestational diabetes. Diabetes care. 1998 Aug;     [PubMed PMID: 9704223]
[11] Felner EI,Klitz W,Ham M,Lazaro AM,Stastny P,Dupont B,White PC, Genetic interaction among three genomic regions creates distinct contributions to early- and late-onset type 1 diabetes mellitus. Pediatric diabetes. 2005 Dec;     [PubMed PMID: 16390390]
[12] Dabelea D,Bell RA,D'Agostino RB Jr,Imperatore G,Johansen JM,Linder B,Liu LL,Loots B,Marcovina S,Mayer-Davis EJ,Pettitt DJ,Waitzfelder B, Incidence of diabetes in youth in the United States. JAMA. 2007 Jun 27;     [PubMed PMID: 17595272]
[13] Gale EA,Gillespie KM, Diabetes and gender. Diabetologia. 2001 Jan;     [PubMed PMID: 11206408]
[14] Mamoulakis D,Galanakis E,Bicouvarakis S,Paraskakis E,Sbyrakis S, Epidemiology of childhood type I diabetes in Crete, 1990-2001. Acta paediatrica (Oslo, Norway : 1992). 2003 Jun;     [PubMed PMID: 12856988]
[15] Tuomilehto J, The emerging global epidemic of type 1 diabetes. Current diabetes reports. 2013 Dec;     [PubMed PMID: 24072479]
[16] Patterson CC,Dahlquist GG,Gyürüs E,Green A,Soltész G, Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet (London, England). 2009 Jun 13;     [PubMed PMID: 19481249]
[17] Vehik K,Hamman RF,Lezotte D,Norris JM,Klingensmith G,Bloch C,Rewers M,Dabelea D, Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes care. 2007 Mar;     [PubMed PMID: 17327312]
[18] Rush T,McGeary M,Sicignano N,Buryk MA, A plateau in new onset type 1 diabetes: Incidence of pediatric diabetes in the United States Military Health System. Pediatric diabetes. 2018 Aug;     [PubMed PMID: 29446519]
[19] Zheng Y,Ley SH,Hu FB, Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature reviews. Endocrinology. 2018 Feb;     [PubMed PMID: 29219149]
[20] Harris MI,Flegal KM,Cowie CC,Eberhardt MS,Goldstein DE,Little RR,Wiedmeyer HM,Byrd-Holt DD, Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Diabetes care. 1998 Apr;     [PubMed PMID: 9571335]
[21] Carter JS,Pugh JA,Monterrosa A, Non-insulin-dependent diabetes mellitus in minorities in the United States. Annals of internal medicine. 1996 Aug 1;     [PubMed PMID: 8686981]
[22] Schulz LO,Bennett PH,Ravussin E,Kidd JR,Kidd KK,Esparza J,Valencia ME, Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S. Diabetes care. 2006 Aug;     [PubMed PMID: 16873794]
[23] Unger RH,Orci L, Paracrinology of islets and the paracrinopathy of diabetes. Proceedings of the National Academy of Sciences of the United States of America. 2010 Sep 14;     [PubMed PMID: 20798346]
[24] Diagnosis and classification of diabetes mellitus. Diabetes care. 2010 Jan;     [PubMed PMID: 20042775]
[25] Standards of medical care in diabetes--2012. Diabetes care. 2012 Jan;     [PubMed PMID: 22187469]
[26] Selph S,Dana T,Bougatsos C,Blazina I,Patel H,Chou R, 2015 Apr;     [PubMed PMID: 25973510]
[27] Karagiannis T,Bekiari E,Manolopoulos K,Paletas K,Tsapas A, Gestational diabetes mellitus: why screen and how to diagnose. Hippokratia. 2010 Jul;     [PubMed PMID: 20981162]
[28] Umpierre D,Ribeiro PA,Kramer CK,Leitão CB,Zucatti AT,Azevedo MJ,Gross JL,Ribeiro JP,Schaan BD, Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. JAMA. 2011 May 4;     [PubMed PMID: 21540423]
[29] Knowler WC,Barrett-Connor E,Fowler SE,Hamman RF,Lachin JM,Walker EA,Nathan DM, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England journal of medicine. 2002 Feb 7;     [PubMed PMID: 11832527]
[30] de Boer IH,Bangalore S,Benetos A,Davis AM,Michos ED,Muntner P,Rossing P,Zoungas S,Bakris G, Diabetes and Hypertension: A Position Statement by the American Diabetes Association. Diabetes care. 2017 Sep;     [PubMed PMID: 28830958]
[31] Aspirin therapy in diabetes. Diabetes care. 2000 Jan;     [PubMed PMID: 12017681]
[32] Ogawa H,Nakayama M,Morimoto T,Uemura S,Kanauchi M,Doi N,Jinnouchi H,Sugiyama S,Saito Y, Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008 Nov 12;     [PubMed PMID: 18997198]
[33] Saito Y,Morimoto T,Ogawa H,Nakayama M,Uemura S,Doi N,Jinnouchi H,Waki M,Soejima H,Sugiyama S,Okada S,Akai Y, Low-dose aspirin therapy in patients with type 2 diabetes and reduced glomerular filtration rate: subanalysis from the JPAD trial. Diabetes care. 2011 Feb;     [PubMed PMID: 21270185]
[34] Holman RR,Paul SK,Bethel MA,Matthews DR,Neil HA, 10-year follow-up of intensive glucose control in type 2 diabetes. The New England journal of medicine. 2008 Oct 9;     [PubMed PMID: 18784090]
[35] Zeller M,Danchin N,Simon D,Vahanian A,Lorgis L,Cottin Y,Berland J,Gueret P,Wyart P,Deturck R,Tabone X,Machecourt J,Leclercq F,Drouet E,Mulak G,Bataille V,Cambou JP,Ferrieres J,Simon T, Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. The Journal of clinical endocrinology and metabolism. 2010 Nov;     [PubMed PMID: 20702526]
[36] Chang CS,Tsai PJ,Sung JM,Chen JY,Ho LC,Pandya K,Maeda N,Tsai YS, Diuretics prevent thiazolidinedione-induced cardiac hypertrophy without compromising insulin-sensitizing effects in mice. The American journal of pathology. 2014 Feb;     [PubMed PMID: 24287404]
[37] Loke YK,Singh S,Furberg CD, Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2009 Jan 6;     [PubMed PMID: 19073651]
[38] Willemen MJ,Mantel-Teeuwisse AK,Straus SM,Meyboom RH,Egberts TC,Leufkens HG, Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase. Diabetes care. 2011 Feb;     [PubMed PMID: 21270195]
[39] Aschner P,Katzeff HL,Guo H,Sunga S,Williams-Herman D,Kaufman KD,Goldstein BJ, Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes, obesity     [PubMed PMID: 20070351]
[40] Unnikrishnan AG,Kalra S,Purandare V,Vasnawala H, Genital Infections with Sodium Glucose Cotransporter-2 Inhibitors: Occurrence and Management in Patients with Type 2 Diabetes Mellitus. Indian journal of endocrinology and metabolism. 2018 Nov-Dec;     [PubMed PMID: 30766827]
[41] Heron M, Deaths: Leading Causes for 2015. National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System. 2017 Nov;     [PubMed PMID: 29235984]
[42] Albers JW,Herman WH,Pop-Busui R,Feldman EL,Martin CL,Cleary PA,Waberski BH,Lachin JM, Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes care. 2010 May;     [PubMed PMID: 20150297]
[43] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998 Sep 12;     [PubMed PMID: 9742976]
[44] Perreault L,Pan Q,Mather KJ,Watson KE,Hamman RF,Kahn SE, Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study. Lancet (London, England). 2012 Jun 16;     [PubMed PMID: 22683134]
[45] Yamazaki D,Hitomi H,Nishiyama A, Hypertension with diabetes mellitus complications. Hypertension research : official journal of the Japanese Society of Hypertension. 2018 Mar;     [PubMed PMID: 29353881]
[46] Wannamethee SG,Shaper AG,Whincup PH,Lennon L,Sattar N, Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors. Archives of internal medicine. 2011 Mar 14;     [PubMed PMID: 21403036]
[47] Rao Kondapally Seshasai S,Kaptoge S,Thompson A,Di Angelantonio E,Gao P,Sarwar N,Whincup PH,Mukamal KJ,Gillum RF,Holme I,Njølstad I,Fletcher A,Nilsson P,Lewington S,Collins R,Gudnason V,Thompson SG,Sattar N,Selvin E,Hu FB,Danesh J, Diabetes mellitus, fasting glucose, and risk of cause-specific death. The New England journal of medicine. 2011 Mar 3;     [PubMed PMID: 21366474]
[48] Stern MP, Do non-insulin-dependent diabetes mellitus and cardiovascular disease share common antecedents? Annals of internal medicine. 1996 Jan 1;     [PubMed PMID: 8554201]
[49] Forbes JM,Cooper ME, Mechanisms of diabetic complications. Physiological reviews. 2013 Jan;     [PubMed PMID: 23303908]
[50] Tseng CH, Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia. 2011 Aug;     [PubMed PMID: 21544514]
[51] Yin M,Zhou J,Gorak EJ,Quddus F, Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. The oncologist. 2013;     [PubMed PMID: 24258613]
[52] Murphy HR,Steel SA,Roland JM,Morris D,Ball V,Campbell PJ,Temple RC, Obstetric and perinatal outcomes in pregnancies complicated by Type 1 and Type 2 diabetes: influences of glycaemic control, obesity and social disadvantage. Diabetic medicine : a journal of the British Diabetic Association. 2011 Sep;     [PubMed PMID: 21843303]
[53] Martínez E,Portillo N,Lizarralde E,Grau G,Vela A,Rodríguez A,Rica I, For Debate: Paediatric T1DM: DKA is Still a Problem. Pediatric endocrinology reviews : PER. 2018 Dec;     [PubMed PMID: 30556656]
[54] Karslioglu French E,Donihi AC,Korytkowski MT, Diabetic ketoacidosis and hyperosmolar hyperglycemic syndrome: review of acute decompensated diabetes in adult patients. BMJ (Clinical research ed.). 2019 May 29;     [PubMed PMID: 31142480]
[55] Sperl-Hillen J,Beaton S,Fernandes O,Von Worley A,Vazquez-Benitez G,Parker E,Hanson A,Lavin-Tompkins J,Glasrud P,Davis H,Adams K,Parsons W,Spain CV, Comparative effectiveness of patient education methods for type 2 diabetes: a randomized controlled trial. Archives of internal medicine. 2011 Dec 12;     [PubMed PMID: 21986350]
[56] Wang TJ,Larson MG,Vasan RS,Cheng S,Rhee EP,McCabe E,Lewis GD,Fox CS,Jacques PF,Fernandez C,O'Donnell CJ,Carr SA,Mootha VK,Florez JC,Souza A,Melander O,Clish CB,Gerszten RE, Metabolite profiles and the risk of developing diabetes. Nature medicine. 2011 Apr;     [PubMed PMID: 21423183]
[57] Lent-Schochet D,Silva R,McLaughlin M,Huet B,Jialal I, Changes to trimethylamine-N-oxide and its precursors in nascent metabolic syndrome. Hormone molecular biology and clinical investigation. 2018 Apr 18;     [PubMed PMID: 29668463]
[58] Reddy P,Leong J,Jialal I, Amino acid levels in nascent metabolic syndrome: A contributor to the pro-inflammatory burden. Journal of diabetes and its complications. 2018 May;     [PubMed PMID: 29559272]
[59] Shim K,Gulhar R,Jialal I, Exploratory metabolomics of nascent metabolic syndrome. Journal of diabetes and its complications. 2019 Mar;     [PubMed PMID: 30611573]
[60] Ramakrishanan N,Denna T,Devaraj S,Adams-Huet B,Jialal I, Exploratory lipidomics in patients with nascent Metabolic Syndrome. Journal of diabetes and its complications. 2018 Aug;     [PubMed PMID: 29895440]