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Introduction

According to the CDC (1), approximately 38.4 million people have diabetes, representing 11.6 percent of the United States population. An additional 97.6 million people over the age of 18 have prediabetes, representing 38% of the United States population. Untreated (or poorly controlled) Diabetes Mellitus has been shown to directly impact all facets of life, from work-related absenteeism and decreased productivity to chronic disability and premature mortality. This chronic medical condition is currently the 8th leading cause of death. 

Early detection and appropriate treatment afford persons with diabetes the best health outcomes. While a diagnosis of diabetes may appear straightforward, many medical conditions can also mimic diabetes in terms of signs/ symptoms, and physical assessment findings. Secondary diabetes can also be caused by complications and side effects of other disease processes, including organ injury, hormonal disturbances, tumors, and medication side effects.  

The goal of this CE program is to discuss various health conditions that can be misdiagnosed as diabetes, their specific assessment findings, and the necessary differential diagnosis to appropriately treat the actual underlying causes of hyperglycemia and diabetic-like symptoms.

Confirmation Testing to confirm a diagnosis of diabetes (2) 

The following laboratory blood tests are used to confirm a diagnosis of prediabetes/ diabetes. These common tests will also be performed in the diagnostic workup for secondary diabetes and hyperglycemia related to other medical conditions. 

Glycated Hemoglobin (Hb) A1C/ A1C  

• Normal range: less than 5.7% 
• Prediabetes range: 5.7%-6.4% 
• Diabetes range:  6.5% or higher 

Fasting Blood Sugar / Fasting Plasma Glucose 

• A blood sample is taken after the person has fasted overnight x 8 hours. 
• Normal Range: below 100mg/dl 
• Prediabetes Range: 100-125mg/dl 
• Diabetes Range: levels greater than 126mg/dl; confirmation testing is done twice, on two separate occasions, especially if the person is asymptomatic. (3) 

Two-Hour Oral Glucose Tolerance Test (OGTT) 

• Plasma glucose levels are measured before and two hours after the ingestion of 75 grams of glucose.  
• Normal Range: less than 140mg/dl 
• Prediabetes Range: 140-199 mg/dl 
• Diabetes confirmation: 200mg/dl or greater.  
• Diabetes is confirmed with a glucose level greater than 200mg/dl. 
• *Patients should not take any medications that may impact glucose tolerance, such as steroids, thiazide diuretics, statins, and beta blockers.  

Random Plasma Glucose Testing (also known as casual glucose testing) 

• Random glucose testing, in patients experiencing symptoms such as polydipsia, polyphagia and polyuria. 
• Results plasma glucose levels greater than 200mg/dl are considered sufficient to diagnose diabetes (although many practitioners prefer additional screenings under more controlled circumstances). 

Primary Types of Diabetes: Pathophysiology, Etiology, and Health Assessment Findings 

Type 1 Diabetes Mellitus 

T1DM accounts for approximately 5-10 percent of all diagnosed cases of diabetes mellitus in the United States. It is believed to be autoimmune; there is no direct link to the development of T1DM, and it most often occurs in children (age 4-9 years old) and early puberty (age 10-14 years old). (4), (5).  

Symptoms of T1DM may include the following: 

• Increased thirst 
• Increased urination 
• Extreme hunger, nausea, and vomiting 
• Unintentional/unexplained weight loss 
• Blurred vision 
• Fatigue, mood changes and irritability 
• Flu-like symptoms. 
• Bedwetting in children who are already successfully potty-trained, frequent full diapers in infants. 
• Slow healing cuts, sores 
• Vaginal yeast infections  

Risk factors for the development of T1DM (6) 

• Family history of diabetes 
• Genetic component 

Diagnosis 

Antibody testing includes: (7), (8) 

One or more of the islet autoantibodies will be present in about 95% of those affected with autoimmune type 1 diabetes at the time of initial diagnosis. With type 2 diabetes, the autoantibodies are typically absent. 

Five common diabetes-related autoantibody tests include: 

• Islet Cell Cytoplasmic Autoantibodies (ICA) 
• Glutamic Acid Decarboxylase Autoantibodies (GADA) 
• Insulinoma-Associated-2 Autoantibodies (IA-2A) 
• Insulin Autoantibodies (IAA) 
• Zinc Transporter-8 Autoantibodies (ZnT8A) 

Diabetic Ketoacidosis 

DKA can occur as the result of untreated/ undertreated diabetes mellitus. Diabetic ketoacidosis is often the first emergent condition to occur that eventually leads to the confirmation of T1DM. 

Symptoms include: 

• Fruity-smelling breath; acetone breath. 
• Abdominal pain, nausea, and vomiting 
• Rapid respirations 
• Drowsiness, confusion, altered levels of consciousness. 
• Flushing of face 
• Dry mucus membranes, dehydration 

DKA confirmation

• Serum glucose level > 250mg/dl 
• Arterial pH < 7.30 
• Serum bicarbonate < 15mEq/l 
• Ketonuria + 
• Elevated anion gap (normal results 4-10 mEq/l)  (9) 
  

T1DM Treatment (10) 

Referral to pediatric endocrinologist for long-term follow-up care. Normal growth and development will necessitate medication adjustments through childhood and adolescence.   

Insulin therapy options available include the following: 

• Multiple daily injections (MDI)  
• Insulin pen 
• Insulin pump 
• Rapid-acting inhaled insulin 

Glucose monitoring options available include the following: 

• Glucose monitoring through a finger stick  
• Continuous glucose monitoring (CGM) devices (skin sensors) 

DSMES (Diabetes Self-Management Education and Support) / Carbohydrate counting/ diabetes emergencies and sick day management.  

• Extensive individual and family/ family support system education to cover all aspects of diabetes self-management, including Section 504 under the Americans with Disabilities Act, to protect the rights of children with diabetes in the school system. (11), (12). 

Type 2 Diabetes Mellitus 

According to the CDC (13), approximately 38 million Americans have diabetes and 90%-95% of them have Type 2 diabetes. Although Type 2 diabetes usually occurs in people over the age of 45, this medical condition can now be detected in younger adults, teenagers, and, sometimes, young children. The rates of childhood obesity are rising, and it is thought that the obesity rates (and lifestyle behaviors attributed to childhood obesity) are directly influencing rates of diabetes. 

In Type 2 diabetes, insulin resistance is thought to be contributing to the increased development of diabetes. Conversely, Type 1 diabetes is considered an autoimmune disease process.  

Risk factors (14) 

• Prediabetes 
• Overweight 
• Are 45 years or older 
• Have a parent, brother, or sister with type 2 diabetes 
• Physically active less than 3 times a week 
• History of gestational diabetes (diabetes during pregnancy) or given birth to a baby who weighed over 9 pounds 
• African American, Hispanic, or Latino, American Indian, or Alaska Native person. Some Pacific Islanders and Asian American people are also at higher risk. 

Symptoms of Type 2 diabetes (15) 

• Increased thirst. (Polydipsia) 
• Frequent urination. (Polyuria) 
• Increased hunger. (Polyphagia) 
• Fatigue. 
• Blurred vision. 
• Slow-healing sores and/or frequent infections. 
• Numbness or tingling in the hands or feet. 
• Areas of darkened skin, usually in the armpits and neck (known as acanthosis nigricans). (16)  

Treatment (17, 18, 19)  

• Lifestyle intervention; behavioral modifications 
• Oral medications: Metformin usually first choice, followed by DDP-4 inhibitors, GLP-1, SGLT2 inhibitors, Sulfonylureas, TZDs 
• Insulin therapy: for initial A1C greater than 10-12 %, consider insulin replacement therapy; for A1C >/- to 7.0% after 2-3 months of dual oral therapy. The initial prescription for Type 2 diabetes is once-daily basal insulin.   
• DSMES patient/family education 
• Dietary /nutrition consultation (calorie and/or carbohydrate controlled, depending on BMI and other comorbid conditions) 

Gestational Diabetes 

Pregnant women, with no personal history of diabetes should be tested for GDM at 24 to 28 weeks of gestation. The American Diabetes Association and American College of Obstetrics and Gynecology (ACOG), as well as the United States Preventive Services Task Force, recommend using either a 1-step or 2-step approach for diagnosing GDM. (20) 

Testing 

One-Step Strategy: 

75 gm OGTT oral glucose tolerance testing 

• Following an overnight fast. 
• Blood samples are collected for 1 hour and 2 hours. 
• GDM is diagnosed if fasting glucose meets or exceeds 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 plasma glucose level at 1 hour after the load is greater than or equal to 140mg/dl (7.8 mmol/l), proceed to step 2. 
• Step 2: 100g 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 to or exceed these cutoffs. 

Treatment 

• Lifestyle behavioral changes (diet and physical activity) 
• Routine blood glucose testing 
• Insulin therapy for glucose regulation  
• Frequent monitoring of gestational growth and development 

Latent autoimmune diabetes in adults (LADA)     

Latent autoimmune diabetes in adults (LADA) is a type of diabetes that develops slowly in adulthood and has signs of both type 1 and type 2 diabetes. LADA is also known as type 1.5 diabetes. (21), (22) 

The Immunology for Diabetes Society (https://www.immunologyofdiabetessociety.com/) has specified three criteria for the diagnosis of LADA: 

• Age greater than 35 years 
• Positive autoantibodies to islet beta cells 
• Insulin independence for at least the initial 6 months after initial diagnosis 

A diagnostic screening tool with three criteria was used to identify LADA in diabetic patients older than 50 years of age: 

• A low or normal BMI. 
• Fasting blood glucose 270 mg/dl or higher, HbA1C 10% or greater despite good compliance. 
• Loss of weight despite a diet constant in calorie content. 

LADA versus Type 2 DM  

T2DM has absent autoantibodies to islet cell components and does not need insulin for an extended period. Glucose control is often achieved by eliminating risk factors and dietary improvement. LADA screening should be considered in patients with T2DM who do not achieve adequate glycemic control within a reasonable period despite compliance to therapy, if they are not obese, lack the features of the MetS (metabolic syndrome), and the patient, nor their first-degree relatives, have other preexisting autoimmune disorders. 

Symptoms usually start in people who have LADA when they are over 30, typically older than people diagnosed with Type 1 diabetes.  In addition, the pancreas is still able to make some insulin at this point, which leads further to a diagnosis of Type 2 diabetes. Persons diagnosed with type 2 diabetes who are lean and physically active, or who have lost weight without effort, could have LADA.  

First, LADA may be managed with lifestyle changes such as exercising regularly, losing weight, making healthy diet choices, and quitting smoking. As the body slowly loses its ability to make insulin; though, most persons with LADA eventually need insulin shots. 

Maturity Onset Diabetes (MODY) 

Also known as Maturity Onset Diabetes of the Young or monogenic diabetes, is a non-insulin dependent version of diabetes mellitus that usually occurs in young adulthood. It is thought to occur due to changes in a genetic mutation and may account for up to 5% of all confirmed cases of diabetes. MODY is often misdiagnosed as either Type 1 or Type 2 diabetes. MODY should be suspected in nonobese persons diagnosed with diabetes at a young age and have a strong familial history of diabetes.  

MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on the causative genetic mutation. Subtypes 1 to 3 account for 95% of cases. Patients with MODY have preserved pancreatic beta-cell function three to five years after diagnosis, as evidenced by detectable serum C-peptide levels with a serum glucose level greater than 144 mg per dL and no laboratory evidence of pancreatic beta-cell autoimmunity. (24) 

Patients with MODY1 and MODY3 have progressive hyperglycemia and vascular complication rates similar to patients with types 1 and 2 diabetes. Lifestyle modification including a low-carbohydrate diet should be the first-line treatment for MODY1 and MODY3. Sulfonylureas are the preferred pharmacologic therapy. Patients with MODY2 have mild stable fasting hyperglycemia with a low risk of diabetes-related complications and generally do not require treatment, except in pregnancy. 

TYPE 2 DIABETES versus MODY

The pathophysiology of MODY involves impaired insulin secretion, whereas type 2 diabetes is characterized by insulin resistance and a progressive loss of beta-cell function.  

 Persons diagnosed with type 2 diabetes who have MODY may exhibit the following: 

• Lack of response to metformin 
• Larger drop in serum glucose level with sulfonylureas 
• Greater sensitivity to insulin 

Maturity-Onset Diabetes of the Young or MODY affects 1-2% of people with diabetes, although it often goes unrecognized. (25) The 3 main features of MODY are: 

• Diabetes often develops before the age of 25. 
• Diabetes runs in families from one generation to the next 
• Diabetes may be treated by diet or tablets and does not always need insulin treatment.

Differential Diagnosis of DM 

The following medical conditions frequently “mimic” diabetes-related symptoms (or cause secondary diabetes) and should be considered in the differential diagnosis of diabetes mellitus.  

Metabolic Syndrome 

Metabolic syndrome (also known as syndrome X or insulin resistance syndrome) is very common in the United States, with approximately 1 out of every 3 persons having the condition. (26) 

Metabolic Syndrome refers to a group of medical conditions, occurring together, that increase a person’s risk for the development of heart disease, stroke, and type 2 diabetes. These five individual conditions include the following: 

• Elevated blood pressure 
• Elevated serum glucose level 
• Excessive body fat accumulation in a person’s waist (abdominal obesity) 
• Elevated serum cholesterol levels 
• Elevated serum triglyceride levels 

Risk factors (27) 

• Age 
• Ethnicity (increased rates of metabolic syndrome are noted in the female Hispanic population) 
• Obesity/overweight 
• Family history of type 2 diabetes; personal history of gestational diabetes 
• Preexisting medical conditions, including nonalcoholic fatty liver disease, polycystic ovarian syndrome, sleep apnea  

Complications (if left untreated): 

• Insulin resistance, progressing to type 2 diabetes mellitus. 
• Cardiovascular disease, including myocardial infarction and cerebral vascular accidents due to ongoing plaque development and arterial disease. 

Diagnostic Criteria 

The National Institutes of Health define metabolic syndrome as having three or more of the following conditions, including conditions that are currently being treated with prescription medication. (A patient history of hypertension, even well controlled with medications, would still be considered a positive (+) finding). (28) 

Lifestyle Recommendations 

• Routine physical activity at least 30 minutes daily 
• Weight loss reduces blood pressure and insulin resistance. Aim for 5-7 percent body weight loss. 
• Dietary intervention- healthy diet intake with an emphasis on fresh fruits/vegetables, high fiber, lean protein, nutrient-dense foods, and lower sodium intake. Decrease intake of sugary-based foods and drinks, heavily processed or refined foods, and saturated and trans-fat foods. DASH diet or Mediterranean Diet  
• Smoking cessation 
• Stress management 
• Proper sleep hygiene practices 

Medication interventions (where applicable) 

• Blood pressure medication 
• Statin therapy to lower triglycerides and cholesterol levels 
• Glucose lowering medications. 

Cushing Disease /Cushing Syndrome 

Cushing disease is a rare condition in which the pituitary gland specifically makes too much adrenocorticotropic hormone (ACTH). It is typically found in the age group 20-50 years old, with women being diagnosed 3x more so than men. Cushing disease is the most common form of Cushing syndrome (29).  

Conversely, Cushing syndrome can occur from excessive (external) cortisol levels related to corticosteroid usage. (30) 

Symptoms (31): 

• Roundness and redness of face/ facial appearance 
• Hump formation on the back of the neck. 
• Stretch marks are visible on the abdomen, chest, and armpit areas. 
• Excessive facial hair growth 
• Excessive bruising is noted on the skin. 
• Weight gain, often rapid and unusual, to the abdominal area. 
• Elevated blood sugar 
• Increased thirst 
• Increased urination 
• High blood pressure (hypertension) 
• Mood changes, anxiety, irritability, headaches  
• Depression 
• Increased number of infections 
• Irregular menstrual periods 

Diagnostics: 

• Serum ACTH and cortisol level 
• Urine cortisol level  
• Saliva cortisol level 
• MRI/CT to confirm the presence of pituitary adenoma. 

Treatment options 

• Medications for Cushing disease/syndrome include: 
• Central-acting inhibitors of ACTH: Pasireotide (Signifor)  
• Adrenal-directed inhibition of steroidogenesis: Medications in this category are used off-label for Cushing disease medications include ketoconazole, metyrapone, mitotane, and etomidate.  
• Glucocorticoid receptor blockade:  mifepristone (Mifeprex)   
• Surgical removal of the tumor 
• Targeted Radiation therapy  

Corticosteroid-Induced Hyperglycemia 

Steroid-induced diabetes (SID) is a unique situation where hyperglycemia occurs secondary to chronic use of steroid medications. As steroids interfere with glucose regulation and insulin metabolism, elevated serum glucose levels occur, often producing the typical diabetes symptoms of polyuria, polydipsia, and polyphagia.  

Persons on long-term steroid therapy, as often seen in medical conditions such as COPD, are at an increased risk of developing SID. Studies have found that 86 percent of people on steroid therapy will experience at least one episode of hyperglycemia. (32)

Neuroleptic-Induced Hyperglycemia 

Neuroleptic-induced diabetes, also known as antipsychotic-induced diabetes, may cause type 2 diabetes in people who take antipsychotic medications. Antipsychotic medication side effects include hyperglycemia and obesity, which increase the risk of diabetes. In addition, these medications directly reduce insulin sensitivity and insulin secretory capacity. (33) 

As the use of antipsychotics rose, reports of substantial weight gain, diabetes, and dyslipidemia began to emerge. Additional studies further linked the increase in diabetes as being multifactorial. Unhealthy food choices, physical inactivity, and social deprivation all contribute to obesity in people with severe mental illness.  

Antipsychotics induce weight gain largely through increased appetite and food intake, in addition to reducing energy expenditure and voluntary movement, in part due to their sedative effects. Although these medications have proven to treat severe mental illness, the risk of diabetes in this population needs to be aggressively monitored with screenings and strategies to ensure early diagnosis and optimal treatment of diabetes to lower the risk of long-term complications.

Infection  

Hyperglycemia can be a normal part of your body’s response to acute stress. Any accident or condition that deeply stresses your body, including sepsis, can cause non-diabetes-related hyperglycemia. When elevated serum glucose levels are related to an accident, injury, or condition, it’s called stress-induced hyperglycemia (SIH), which is a glucose level greater than 180mg/dl in persons who do not have a history of diabetes. (34) 

SIH occurs when counterregulatory hormones (cortisol, glucagon, and catecholamines) disturb the glucose hemostasis. This results in insulin resistance and hyperglycemia. Statistically, hyperglycemia in critically ill patients (ICU-based) is an observed finding evident in the first 48 hours of admission in at least 50% of the patients. (35) 

Treatment 

• Insulin coverage sliding scale/ insulin infusion per ICU protocol. 
• Nutrition consults to ensure diet (if applicable) is optimal to avoid overfeeding/ excessive glucose intake (avoid prolonged fasting state) 
• Follow-up with a primary doctor to ensure diabetes screenings/ hyperglycemia surveillance. 
• DSMES classes on nutritional therapy, exercise, and smoking cessation to delay onset of prediabetes/ diabetes.

Pheochromocytoma            

Pheochromocytoma is a rare, catecholamine-secreting tumor that originates from the adrenal medulla and can cause glucose intolerance or diabetes mellitus. This occurs as beta-receptors stimulate gluconeogenesis, while alpha-2 receptors decrease insulin release. 60.78% of patients with pheochromocytoma also have diabetes or glucose intolerance. The increase in catecholamine levels is associated with decreased glucose uptake and increased gluconeogenesis and glycogenolysis. (36) 

Persons with a diagnosis of pheochromocytoma should be screened for diabetes, especially if other risk factors are present. The removal of a pheochromocytoma reduces insulin secretion and peripheral insulin resistance, making early diagnosis important. 

Symptoms (37, 38) 

• Hypertension/ orthostatic hypertension  
• Headache 
• Irregular heart rates 
• Feelings of anxiety 
• Nausea/ vomiting/ diarrhea 
• Unexplained weight loss 
• Glucose intolerance pre-op (due to catecholamine release); severe hypoglycemia post-op tumor removal (due to abrupt tumor removal) 

Diagnosis 

• 24-hour urine test catecholamine level 
• Serum catecholamine level 
• CT/ MRI imaging of adrenal glands 

Iron Overload (Hemochromatosis) 

Iron overload disorder may be caused by genetics or as the result of another disease/ medical condition. Hereditary hemochromatosis is the result of a genetic component; secondary hemochromatosis may result from excessive dietary intake of iron, numerous blood transfusions, and various blood disorders such as sickle cell disease or thalassemia. Left undiagnosed and untreated, excessive accumulation of iron in the pancreas can interfere with insulin production, leading to diabetes mellitus. (39) 

Symptoms may include the following:  

• Chronic fatigue and weakness 
• Abdominal pain, possible pancreatitis 
• Joint pain, possible arthritis  
• Irregular heart rate, possible heart disease 
• Enlargement of liver, possible cirrhosis  

Diagnosis 

• Blood tests, including ferritin and transferrin saturation levels. 
• Liver scans, abdominal scans (CT, MRI) 
• Genetic testing when applicable 

Treatment 

• Phlebotomy is routinely scheduled, to reduce the severity levels of iron overload. 
• Chelation therapy 
• Hemochromatosis diet to focus on the reduced intake of iron-rich/iron-fortified foods (including dietary supplements) 

The Importance of DSMES (Diabetes Self-Management Education and Support) 

What next? After a confirmed diagnosis of diabetes mellitus, regardless of the underlying cause, all patients should be referred to a structured diabetes management program. In doing so, you as a healthcare professional will afford your patient the best opportunity to gain the knowledge and skills necessary to effectively manage this chronic medical condition.  

DSMES programs, often covered by insurance plans including Medicare (Medicare covers up to 10 hours of diabetes education for people diagnosed in the past year), offer the person with diabetes the practical skills, knowledge, and insights to address all avenues of diabetes. In doing so, they gain self-confidence, lower risk factors and complications, reduce hospitalizations, and improve the quality of their life. 

Referrals to DSMES should take place at the time of diagnosis when new health concerns arise, and any time life changes/events interfere with ongoing chronic disease management. By giving your patient, the knowledge, and skills necessary to manage their diabetes, short- and long-term complication risk is lowered, as well as unnecessary trips to the emergency department/hospital. (43)

Conclusion

As stated in the introduction of this course, cases of diabetes mellitus continue to increase throughout the world. Early stages of this medical condition may not be detected through symptoms alone, yet left untreated, can affect long-term health and well-being. While 38.1 million adults were diagnosed with diabetes in 2021, another 8.7 million adults had diabetes but were undiagnosed. 

The argument for annual screenings (routine, preventive) is justified to reduce the worldwide crisis in terms of healthcare dollars spent for direct medical costs as well as reduced productivity due to poor diabetes-related outcomes (long-term disability associated with nontraumatic amputations, as well as kidney and eye disease. (40), (41) 

Untreated/ undiagnosed diabetes can wreak havoc on the health and well-being of an individual. Early treatment and intervention afford a person the best chance at achieving optimal glucose levels and lowering the risk of long-term, often life-threatening complications. Annual diabetes screenings, especially in high-risk populations/ persons afford the best opportunity for early detection and treatment. 

 Consider preventive screenings/ routine diabetes surveillance in the following populations: 

• Persons 45 years of age  
• 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 or hypertension 
• Low HDL-cholesterol or hypertriglyceridemia 
• Women with polycystic ovarian syndrome 
• Physical inactivity 
• Conditions associated with insulin resistance. 
• Women diagnosed with gestational diabetes mellitus (GDM) should have lifelong testing at least every three years. (Approximately 50 % of women diagnosed with GDM will go on to develop Type 2 diabetes within 3-6 years. (42) 

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