Diabetes Mellitus A Silent Killer

BY MIAN A. JAN, M.D., F.A.C.C., F.S.C.A.I., AND AHMED SHAMSI

Introduction

Diabetes mellitus (DM) is a chronic metabolic disease characterized by elevated blood glucose levels (hyperglycemia). DM may result from defects in insulin secretion, resistance to insulin action, or both. Approximately 537 million adults (2079 years) had diabetes in 2021 according to the International Diabetes Federation (IDF), with a projected rise to 643 million adults by 2031. Progression of diabetes mellitus results in tissue and blood vessel damage leading to severe complications including retinopathy, neuropathy, and nephropathy as well as cardiovascular complications. Diabetes mellitus is a silent killer, with approximately 7.3 million U.S. adults who met laboratory criteria for diabetes not being aware of or reporting having diabetes.

Etiology

In the pancreas, there are two major classes of hormoneproducing cells: the insulin-secreting beta cells, and the glucagonsecreting alpha cells. Insulin induces muscle and liver cells to take up glucose, decreasing blood glucose concentration, whereas glucagon serves to increase the concentration of blood glucose. Without the balance of insulin and glucagon, glucose levels will reach improper concentrations. In the case of diabetes mellitus, insulin is either absent, or there is receptor level resistance to the effects of insulin, leading to hyperglycemia.

The vast majority of diabetes cases fall into two broad categories by etiology: type 1 diabetes, and type 2 diabetes.

Type 1 Diabetes Mellitus (T1DM)

Type 1 diabetes mellitus (T1DM) accounts for 5-10% of those with diabetes. T1DM is characterized by the destruction of beta cells in the pancreas, resulting in absent or extremely low insulin production. Markers of the destruction of beta cells include antibodies against islet cells, insulin, glutamic acid decarboxylase-65 (GAD-65), and tyrosine phosphatases IA-2 and IA-2ß. At least one of these autoantibodies is present in 85-90% of individuals when fasting hyperglycemia is initially detected. This form of diabetes most commonly occurs in children and adolescents and is associated with genetic predisposition and environmental factors such as viruses or toxins.

Type 2 Diabetes Mellitus (T2DM)

Type 2 diabetes mellitus (T2DM) is far more frequent than T1DM, accounting for 90% to 95% of those with diabetes. T2DM is characterized by a diminished response to insulin by muscle, fat, and liver cells, which is termed insulin resistance. Insulin resistance is initially countered by an increased production of insulin by the pancreas to maintain normal blood glucose levels. Over time, however, insulin production decreases and type 2 diabetes mellitus is diagnosed. T2DM is often undiagnosed for many years due to the gradual development of hyperglycemia, and early symptoms that are not severe enough to be recognized by patients. The risk of developing T2DM increases with age, obesity, and physical inactivity, and is associated with a strong genetic predisposition.

Epidemiology

Diabetes mellitus is a global epidemic with 1 in 10 adults affected worldwide. T1DM may be diagnosed at any age, however, it peaks at 5-7 years of age and again at 10-14 years of age. Unlike most autoimmune diseases, which disproportionately affect women, type 1 diabetes affects both males and females equally. The incidence and prevalence of T1DM is increasing in the world, with data from international epidemiological studies indicating a rate of increase of 2-5%.

Type 2 diabetes mellitus continues to increase with the increasing rates of obesity and sedentary lifestyles. The onset of T2DM is most common in persons older than 45 years, although obesity in adolescents has led to an increase in T2DM in younger groups. Globally, an estimated 462 million individuals are affected by T2DM. A high incidence of microvascular complications is found in individuals with T2DM with half of patients presenting such complications. Cardiovascular disease, including coronary heart disease, cerebrovascular disease, and peripheral vascular disease, typically develops 14.6 years earlier in patients with T2DM, and with a greater severity, than individuals without DM. Type 2 diabetes mellitus varies among ethnic groups with Asians, African Americans, and Latinos having a higher prevalence than whites in the United States.

Pathophysiology

T1DM is characterized by the autoimmune destruction of pancreatic beta cells by activated macrophages, CD4+ T cells and CD8+ T cells which infiltrate the islets. Islet cell antibodies are present in 85% of patients with a majority of these patients also having anti-insulin antibodies. These islet cell antibodies are usually directed against glutamic acid decarboxylase (GAD) in pancreatic beta cells. The destruction of beta cells in the pancreas leads to absent or extremely low insulin production, resulting in the metabolic derangements characterized by T1DM. The destruction of beta cells is coupled with the abnormal function of alpha cells which secrete excess glucagon, exacerbating the metabolic defects of insulin deficiency.

T2DM is characterized by two pathological defects: insulinresistance and associated beta cell dysfunction. Initially, insulin resistance is compensated as beta cells undergo a transformation capable of increasing insulin supply. Over time, however, due to decreased insulin production or increased insulin resistance, glucose homeostasis cannot be maintained, and T2DM is diagnosed. The majority of obese individuals have insulin resistance, a consequence of adipose tissue release of excess free fatty acids (FFAs), reactive oxygen species (ROS), and proinflammatory cytokines.

History and Physical

DM is often presented asymptomatically, underscoring the dangerous nature of this metabolic disease. When symptoms do develop, patients commonly present increased urination, increased thirst, and weight loss. Patients with prolonged hyperglycemia may experience blurred vision and numbness in the hands and feet. Type 1 and type 2 diabetes can be distinguished based on the patient’s clinical history and examination. The majority of patients with T2DM are overweight/obese and present signs of insulin resistance including patches of dark, velvety skin known as acanthosis nigricans. Patients must be tested for retinopathy, neuropathy, and pulses should be examined to check for peripheral arterial disease.

Evaluation

Tests utilized to diagnose DM include Fasting Plasma Glucose (FPG), Two-Hour Oral Glucose Tolerance Test (OGTT), and Glycated Hemoglobin (Hb) A1C. An FPG tests glucose levels after an eight hour fast and is usually done in the morning. An OGTT checks glucose levels before and two hours after an ingestion of 75 gm of glucose. Hb A1C measures blood glucose level over the previous 2 to 3 months. According to the American Diabetes Association, diabetes is diagnosed at a fasting blood sugar of greater than or equal to 126 mg/dl, a 2-hour blood sugar greater than or equal to 200 mg/dl, and an A1C of greater than or equal to 6.5%.

Treatment/Management

T1DM is primarily treated through insulin administration, either through injections or insulin pumps. The majority of T2DM patients are overweight/obese, and so initial treatments center around a healthy diet and caloric restriction as well as regular exercise and monitoring of glucose. Prescribed diabetic medications may be utilized with metformin being the first line of treatment. The use of metformin may be followed by other therapies that target insulin secretion or insulin sensitivity including sulfonylureas, dipeptidyl peptidase IV inhibitors continued on next page >

(DPP-4), Glucagon-like-peptide-1 (GLP-1) receptor agonists, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, selective amylinomimetics, and sodium-glucose transporter-2 (SGLT-2) inhibitors. Bariatric surgery may normalize glucose levels in morbidly obese patients but is only recommended for individuals who are unresponsive to other treatments.

Microvascular screenings should be performed regularly including retinal exams to test for diabetic retinopathy and neurologic examination to identify patients with neuropathy. Diabetic peripheral neuropathic pain may be treated with FDA approved medications pregabalin and duloxetine and with anticonvulsant and antidepressant drugs. Urine albumin excretion should be undertaken at least twice a year.

Regular blood pressure screening for diabetics is also recommended. The goal blood pressure should be less than 130/85. Treatment for hypertensive diabetics includes ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, and/or calcium channel blockers. Lipid monitoring should also be performed with a goal LDL-C less than 100mg/dl if there is no atherosclerotic cardiovascular disease (ASCVD). If ASCVD is present, LDL-C should remain below 70mg/dl. Statins are primarily utilized to lower cholesterol and are linked to lower risk of heart disease and stroke.

Differential Diagnoses

Certain diseases and conditions may present similar clinical features and symptoms to diabetes mellitus. An education of these conditions is pertinent to make an accurate diagnosis. These conditions include: •Glucocorticoid-induced hyperglycemia •Hormonal syndromes including cushing syndrome, pheochromocytoma, acromegaly, glucagonoma •Conditions damaging the pancreas, including pancreatitis, pancreatic cancer, cystic fibrosis, hemochromatosis •Thyroid disorders

Prognosis

As of 2020, diabetes mellitus is the 8th leading cause of death in the United States. Patients with diabetes are twice as likely to experience heart disease or a stroke than individuals not affected with DM. Diabetic neuropathy affects approximately 50% of patients, and vision-threatening retinal complications will develop over time in 50% of T1DM patients and 30% of T2DM patients. Treatment with drugs for hyperglycemia, managing blood pressure, and lowering LDL cholesterol are key in preventing vascular complications and slowing disease progression to reduce morbidity and mortality.

Complications

Several complications may occur in uncontrolled diabetes mellitus including microvascular and macrovascular conditions. DM is a leading cause of heart disease, blindness, kidney disease, nerve damage, and amputations in the lower limbs. Microvascular complications include nephropathy, neuropathy, and retinopathy, and affect approximately half the patients with T2DM. Macrovascular complications of T2DM include coronary artery disease, arrythmias, cerebrovascular disease, and peripheral artery disease.

Deterrence and Patient Education

Patients should be educated on glycemic control and lifelong lifestyle changes to reduce complications associated with diabetes mellitus. Diet and exercise must be stressed as well as quitting smoking and minimizing alcohol consumption. Checking of blood glucose daily, regular estimation of glycated hemoglobin and LDL levels, and taking medications as prescribed are important steps for patients wanting to take responsibility of managing their diabetes.

Summary

“I may have diabetes but diabetes does not have me.” Elise Quarrington

I think this quote should be the basis of management of DM. A step by step approach starting with a correct diagnosis followed by diet and exercise program. If these modalities are unsuccessful then add drugs as described in the body of the article.

A team approach between general practitioners and specialists is the best way of dealing with this very complex and devastating pathology.

This article was written by Mian A. Jan, M.D., Chairman, Department of Medicine Penn Medicine Chester County Hospital, and Ahmed Shamsi, an intern at West Chester Cardiology.