Diabetes Mellitus (DM)

• Autoimmune pancreatic beta-cell destruction and absent insulin production

Type 1 accounts for < 10% of all cases of diabetes mellitus.

In type 1 diabetes mellitus (previously called juvenile-onset or insulin-dependent), insulin production is absent because of autoimmune pancreatic beta-cell destruction possibly triggered by an environmental exposure in people who are genetically susceptible. Destruction progresses subclinically over months or years until beta-cell mass decreases to the point that insulin concentrations are no longer adequate to control plasma glucose levels. Type 1 diabetes generally develops in childhood or adolescence and until recently was the most common form diagnosed before age 30; however, it can also develop in adults.

Autoimmune diabetes that develops in adulthood is often more slowly progressive than childhood type 1 diabetes. Some adults do not need insulin when dysglycemia first develops. This form of diabetes, called latent autoimmune diabetes of adulthood (LADA), may initially be diagnosed as type 2 diabetes.

Some cases of type 1 diabetes do not appear to be autoimmune in nature and are considered idiopathic.

The pathogenesis of the autoimmune beta-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors.

Susceptibility genes include those within the major histocompatibility complex (MHC)—especially HLA-DR3,DQB1*0201 and HLA-DR4,DQB1*0302, which are present in > 90% of patients with type 1 diabetes mellitus—and those outside the MHC, which seem to regulate insulin production and processing and confer risk of diabetes mellitus in concert with MHC genes. Susceptibility genes are more common among some populations than among others and explain the higher prevalence of type 1 diabetes in people with ancestry from certain areas (eg, Scandinavians, Sardinians).

Autoantigens include glutamic acid decarboxylase, insulin, proinsulin, insulinoma-associated protein, zinc transporter ZnT8, and other proteins in beta cells. It is thought that these proteins are exposed or released during normal beta-cell turnover or beta-cell injury (eg, due to infection), activating primarily a T cell‒mediated immune response that results in beta-cell destruction (insulitis). Glucagon-secreting alpha cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of) beta-cell destruction.

Several viruses (including coxsackievirus, rubella virus, cytomegalovirus, Epstein-Barr virus, SARS-CoV-2 (1, 2), and retroviruses) have been linked to the onset of type 1 diabetes. Viruses may directly infect and destroy beta cells, or they may cause beta-cell destruction indirectly by exposing autoantigens, activating autoreactive lymphocytes, mimicking molecular sequences of autoantigens that stimulate an immune response (molecular mimicry), or other mechanisms.

Diet may also be a factor. Exposure of infants to dairy products (especially cow’s milk and the milk protein beta casein), high nitrates in drinking water, and low vitamin D consumption have been linked to increased risk of type 1 diabetes. Early (< 4 months) or late (> 7 months) exposure to gluten and cereals increases islet cell autoantibody production. Mechanisms for these associations are unclear.

• Resistance to insulin

In type 2 diabetes mellitus (previously called adult-onset or non–insulin-dependent), insulin secretion is inadequate because patients have developed resistance to insulin. Hepatic insulin resistance leads to an inability to suppress hepatic glucose production, and peripheral insulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. Often insulin levels are very high, especially early in the disease. Later in the course of the disease, insulin production may fall, further exacerbating hyperglycemia.

The disease generally develops in adults and becomes more common with increasing age; up to one third of adults > age 65 years have impaired glucose tolerance. In older adults, plasma glucose levels reach higher levels after eating than in younger adults, especially after meals with high carbohydrate loads. Glucose levels also take longer to return to normal, in part because of increased accumulation of visceral and abdominal fat and decreased muscle mass.

Type 2 diabetes has become more common among children because childhood obesity has become epidemic. More than 90% of adults with diabetes have type 2 disease. There are clear genetic determinants, as evidenced by the high prevalence of the disease in relatives of people with the disease. Although several genetic polymorphisms have been identified, no single gene responsible for the most common forms of type 2 diabetes has been identified.

Pathogenesis is complex and incompletely understood. Hyperglycemia develops when insulin secretion can no longer compensate for insulin resistance. Although insulin resistance is characteristic in people with type 2 diabetes and those at risk of it, evidence also exists for beta-cell dysfunction and impaired insulin secretion that progresses over time, including

• Impaired first-phase insulin secretion

• A loss of normally pulsatile insulin secretion

• An increase in proinsulin secretion signaling, indicating impaired insulin processing

• An accumulation of islet amyloid polypeptide (a protein normally secreted with insulin)

Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize beta cells, cause beta-cell dysfunction (glucose toxicity), or both.

Obesity and weight gain are important determinants of insulin resistance in type 2 diabetes. They have some genetic determinants but also reflect diet, exercise, and lifestyle. An inability to suppress lipolysis in adipose tissue increases plasma levels of free fatty acids that may impair insulin-stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also functions as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-alpha, interleukin-6, leptin, resistin) influence glucose metabolism.

Intrauterine growth restriction and low birth weight have also been associated with insulin resistance in later life and may reflect adverse prenatal environmental influences on glucose metabolism.

Miscellaneous types of diabetes mellitus account for a small proportion of cases. Causes include

• Monogenic diabetes due to genetic defects affecting beta-cell function, insulin action, or mitochondrial DNA (eg, maturity-onset diabetes of youth, neonatal diabetes)

• Conditions that affect the pancreas (eg, cystic fibrosis, pancreatitis, hemochromatosis, pancreatectomy)

• Endocrinopathies (eg, Cushing syndrome, acromegaly)

• Medications, most notably glucocorticoids, beta-blockers, protease inhibitors, atypical antipsychotics, immune checkpoint inhibitors, and calcineurin inhibitors

Pregnancy causes some insulin resistance in all women, but only a fraction will develop gestational diabetes.

1. 1. Anindya R, Rutter GA, Meur G. New-onset type 1 diabetes and severe acute respiratory syndrome coronavirus 2 infection. Immunol Cell Biol 2023;101(3):191-203. doi:10.1111/imcb.12615

2. 2. D'Souza D, Empringham J, Pechlivanoglou P, Uleryk EM, Cohen E, Shulman R. Incidence of Diabetes in Children and Adolescents During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis. JAMA Netw Open 2023;6(6):e2321281. doi:10.1001/jamanetworkopen.2023.21281

All patients with type 1 diabetes mellitus should begin screening for diabetic complications 5 years after diagnosis. For patients with type 2 diabetes, screening begins at diagnosis. Typical monitoring for complications includes

• Foot examination

• Funduscopic examination

• Urine testing for albuminuria

• Measurement of serum creatinine and lipid profile

Foot examination should be done at least annually for impaired sense of pressure, vibration, pain, or temperature, which is characteristic of peripheral neuropathy. Pressure sense is best tested with a monofilament esthesiometer (see figure Diabetic Foot Screening). The entire foot, and especially skin beneath the metatarsal heads, should be examined for skin cracking and signs of ischemia or infection, such as ulcerations, gangrene, fungal nail infections, deceased pulses, and hair loss.

Funduscopic examination should be done by an ophthalmologist; the screening interval is typically annually for patients with any retinopathy to every 2 years for those without retinopathy on a prior examination. If retinopathy shows progression, more frequent evaluation may be needed.

Spot or 24-hour urine testing is indicated annually to detect albuminuria, and serum creatinine should be measured annually to assess kidney function.

Testing for cardiovascular disease is needed. Many physicians consider baseline ECG important given the risk of heart disease. Lipid profile should be checked at least annually and more often when abnormalities are present. Blood pressure should be measured at every examination.

1. 1. American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 46 (Supplement 1): 1-291, 2023.

2. 2. Holt RIG, DeVries JH, Hess-Fischl A, et al: The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 64(12):2609–2652, 2021. doi: 10.1007/s00125-021-05568-3

(See also Medication Treatment of Diabetes.)

All patients with type 1 diabetes require . The goal is to try to replicate the pattern of insulin secretion of a person who does not have diabetes by using basal-bolus insulin therapy. In basal-bolus therapy, a longer-acting insulin (or a continuous subcutaneous infusion of rapid-acting insulin delivered by a pump) is used to simulate basal insulin production that suppresses hepatic glucose production, especially in the fasting state, and a shorter-acting insulin is used before meals to control postprandial glucose excursions.

Sliding-scale insulin is a strategy in which varying doses of rapid-acting insulin are given before meals and at bedtime depending on the patient's plasma glucose level. However, a sliding scale insulin regimen on its own is not an effective strategy for maintaining euglycemia in patients with type 1 diabetes or in most patients with type 2 diabetes.

Patients with type 2 diabetes and mildly elevated plasma glucose may be prescribed a trial of diet and exercise, followed by a insulin therapy should be initiated in patients with more significant glucose elevations at diagnosis or with HbA1C levels 1.5 to 2.0% above target. There is evidence that early combination medication therapy leads to superior and more durable blood glucose control than a stepwise approach to adding diabetes pharmacotherapy (1). Goals and monitoring are discussed below.

Glucagon-like peptide-1 (GLP1) receptor agonists are an effective second-line therapy after metformin and may be more effective than insulin, or as an add-on to insulin

In patients with atherosclerotic cardiovascular disease, a sodium/glucose cotransporter 2 (SGLT2) inhibitor or a GLP-1 receptor agonist may be recommended because of evidence that these medication classes decrease major adverse cardiovascular events (eg, myocardial infarction, stroke) and mortality. In patients with chronic kidney disease (2, 3) or heart failure (4metabolic associated steatotic liver disease (formerly nonalcoholic fatty liver disease) or metabolic associated steatohepatitis (formerly nonalcoholic steatohepatitis).

Insulin is indicated as initial therapy for women with type 2 diabetes who are pregnant and for patients who present with acute metabolic decompensation, such as hyperosmolar hyperglycemic state or diabetic ketoacidosis (DKA). Insulin should be considered in patients with evidence of ongoing catabolism (weight loss) or symptoms of hyperglycemia (ie, polyuria, polydipsia) and/or with HbA1C levels > 10% and blood glucose levels ≥ 300 mg/dL (16.7 mmol/L). Patients with severe hyperglycemia may respond better to therapy after glucose levels are normalized with insulin treatment.

Education is crucial to optimizing care. Education should include information about the following:

• Causes of diabetes

• Diet

• Exercise

• Medications

• Self-monitoring with fingerstick testing or continuous glucose monitoring

• Monitoring HbA1C

• Symptoms and signs of hypoglycemia, hyperglycemia, and diabetic complications

Most patients with type 1 diabetes can be taught how to adjust their insulin doses based on blood glucose levels and carbohydrate intake. Education should be reinforced at every physician visit and hospitalization. Formal diabetes education programs, generally conducted by diabetes nurses and nutrition specialists, are often very effective and have been shown to improve diabetes outcomes.

Adjusting diet to individual circumstances can help patients control fluctuations in their glucose level and, for patients with type 2 diabetes mellitus, lose weight. Dietary recommendations should be individualized based on patient tastes, preferences, culture, and goals and should be formulated to accommodate requirements posed by comorbid conditions. There are no recommendations on the percentages of calories that should come from carbohydrate, protein, or fat. Patients should be educated on consuming a diet rich in whole foods rather than processed foods. Carbohydrates should be high quality and should contain adequate amounts of fiber, vitamins, and minerals and be low in added sugar, fat, and sodium. Some adults can reduce blood glucose levels and decrease antihyperglycemic medications by following a low- or very-low–carbohydrate eating plan, although maintaining such a diet can be challenging and the benefits may not be sustained long-term. 

Patients with type 1 diabetes should use carbohydrate counting or the carbohydrate exchange system to match insulin dose to carbohydrate intake and facilitate physiologic insulin replacement. “Counting” the amount of carbohydrate in the meal is done to calculate the preprandial insulin dose. For example, if a carbohydrate-to-insulin ratio (CIR) of 15 gram:1 unit is used, a patient will require 1 unit of rapid-acting insulin for each 15 g of carbohydrate in a meal. These ratios can vary significantly between patients, depending on their degree of insulin sensitivity and must be tailored to the patient and adjusted over time. Patients should also be educated that meals with higher protein or fat content can increase insulin requirements and dose adjustments may be necessary. This approach requires detailed patient education and is most successful when guided by a dietitian experienced in working with patients with diabetes. Some experts have advised use of the glycemic index (a measure of the impact of an ingested carbohydrate-containing food on the blood glucose level) to delineate between rapid and slowly metabolized carbohydrates, although there is little evidence to support this approach.

For both type 1 diabetes and type 2 diabetes, nutrition consultation with a dietitian should complement physician counseling; the patient and any person who prepares the patient’s meals should be present.

Physical activity should increase incrementally to whatever level a patient can tolerate. Both aerobic exercise and resistance exercise have been shown to improve glycemic control in type 2 diabetes, and several studies have shown a combination of resistance and aerobic exercise to be superior to either alone (5, 6, 7). In type 1 diabetes, exercise has been shown to decrease mortality although the effect on HbA1C lowering is less clear (8, 9, 10). Adults with diabetes and without physical limitations should exercise for a minimum of 150 minutes/week (divided over at least 3 days). Exercise has a variable effect on blood glucose, depending on the timing of exercise in relation to meals and the duration, intensity, and type of exercise. In patients with type 1 diabetes in particular, exercise can lead to hypoglycemia. Therefore, blood glucose should be monitored immediately before and after exercise. The target range for blood glucose prior to exercise should be between 90 mg/dL and 250 mg/dL (5 mmol/L to 14 mmol/L).

Patients who experience hypoglycemic symptoms during exercise should be advised to test their blood glucose and ingest carbohydrates or lower their insulin dose as needed to get their glucose slightly above normal just before exercise. Hypoglycemia during vigorous exercise may require carbohydrate ingestion during the workout period, typically 5 to 15 g of sucrose or another simple sugar.

Patients with known or suspected cardiovascular disease may benefit from exercise stress testing before beginning an exercise program. Activity goals may need to be modified for patients with complications of diabetes such as neuropathy and retinopathy.

In people with diabetes and obesityMedication Treatment of Diabetes

An oral hydrogel containing cellulose and citric acid that causes patients to feel full and eat less can induce modest weight loss in patients with prediabetes and diabetes.

Medical devices, including implanted gastric balloons, a vagus nerve stimulator, and gastric aspiration therapy, are also available, but their use remains limited due to high cost and limited data in patients with diabetes.

Surgical treatment for obesity, such as sleeve gastrectomy or gastric bypass, also leads to weight loss and improvement in glucose control (independent of weight loss) and decreased cardiovascular risk in patients who have diabetes mellitus and should be recommended for appropriately selected patients.

Shoes should fit well, be wide-toed without open heels or toes, and be changed frequently. Special shoes should be prescribed to reduce trauma if the foot is deformed (eg, previous toe amputation, hammer toe, bunion). Walking barefoot should be avoided.

Patients with neuropathic foot ulcers should avoid weight bearing until ulcers heal. If they cannot, they should wear appropriate orthotic protection. Because most patients with these ulcers have little or no macrovascular occlusive disease, debridement and antibiotics frequently result in good healing and may prevent major surgery. After the ulcer has healed, appropriate inserts or special shoes should be prescribed. In refractory cases, especially if osteomyelitis is present, surgical removal of the metatarsal head (the source of pressure), amputation of the involved toe, or transmetatarsal amputation may be required. A neuropathic joint can often be satisfactorily managed with orthopedic devices (eg, short leg braces, molded shoes, sponge-rubber arch supports, crutches, prostheses).

All patients with diabetes mellitus should be vaccinated against Streptococcus pneumoniae, influenza virus, hepatitis B, varicella, and SARS-CoV-2 as per standard recommendations.

Pancreas transplantation and transplantation of pancreatic islet cells are alternative means of insulin delivery (11, 12); both techniques effectively transplant insulin-producing beta-cells into patients who are insulin deficient (have type 1 diabetes mellitus).

1. 1. Matthews DR, Paldánius PM, Proot P, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 2019;394(10208):1519-1529. doi:10.1016/S0140-6736(19)32131-2

2. 2. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022;400(10365):1788-1801. doi:10.1016/S0140-6736(22)02074-8

3. 3. Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials [published correction appears in BMJ 2022 Jan 18;376:o109]. BMJ 2021;372:m4573. Published 2021 Jan 13. doi:10.1136/bmj.m4573

4. 4. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials [published correction appears in Lancet 2023 Jan 14;401(10371):104]. Lancet 2022;400(10354):757-767. doi:10.1016/S0140-6736(22)01429-5

5. 5. Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial [published correction appears in JAMA 2011 Mar 2;305(9):892]. JAMA 2010;304(20):2253-2262. doi:10.1001/jama.2010.1710

6. 6. Colberg SR, Sigal RJ, Yardley JE, et al. Physical Activity/Exercise and Diabetes: A Position Statement of the American Diabetes Association. Diabetes Care 2016;39(11):2065-2079. doi:10.2337/dc16-1728

7. 7. Sigal RJ, Kenny GP, Boulé NG, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med 2007;147(6):357-369. doi:10.7326/0003-4819-147-6-200709180-00005

8. 8. Bohn B, Herbst A, Pfeifer M, et al. Impact of Physical Activity on Glycemic Control and Prevalence of Cardiovascular Risk Factors in Adults With Type 1 Diabetes: A Cross-sectional Multicenter Study of 18,028 Patients. Diabetes Care 2015;38(8):1536-1543. doi:10.2337/dc15-0030

9. 9. Pongrac Barlovic D, Harjutsalo V, Groop PH. Exercise and nutrition in type 1 diabetes: Insights from the FinnDiane cohort. Front Endocrinol (Lausanne) 2022;13:1064185. doi:10.3389/fendo.2022.1064185

10. 10. Shorey S, Ng ED, Law EC, Wong JCM, Loke KY, Tam WWS. Physical Activity and Nutrition Interventions for Type 1 Diabetes: A Meta-analysis. Pediatrics 2022;150(3):e2022056540. doi:10.1542/peds.2022-056540

11. 11. Dean PG, Kukla A, Stegall MD, et al: Pancreas transplantation. BMJ 3:357, 2017. doi: 10.1136/bmj.j1321

12. 12. Rickels MR, Robertson RP: Pancreatic islet transplantation in humans: Recent progress and future directions. Endocr Rev 40(2):631–668, 2019. doi: 10.1210/er.2018-00154

Fingerstick glucose monitors measure capillary blood glucose. Many different glucose meters are available. Nearly all require test strips and a means for pricking the skin and obtaining a blood sample. Choice among devices is usually based on patient preferences for features such as time to results (usually 5 to 30 seconds), size of display panel (large screens may benefit patients with poor eyesight), voice readout (for those with visual impairment), and smartphone app connectivity (2).

Continuous glucose monitoring (CGM) systems estimate capillary blood glucose from interstitial glucose detected by a subcutaneous sensor. They can either provide glucose measurements continuously (real-time CGM) or intermittently when scanned with a device (intermittently scanned CGM). CGMs provide real-time glucose data including an alarm to warn of hypoglycemia, hyperglycemia, or rapidly changing glucose levels.

Although CGMs have less stringent accuracy requirements than capillary blood glucose monitors, they allow users and clinicians to assess for patterns of hyperglycemia and hypoglycemia that are not identified with fingerstick glucose monitoring. Use of CGMs has been shown to increase patients' time in target range (TIR) and decrease HbA1C (3, 4, 5). Use of CGMs is recommended for all patients who are treated with intensive insulin therapy and can use the devices safely (6).

For patients with diabetes who use CGMs, TIR is defined as the percentage of time blood glucose measurement on CGM is within the target blood glucose range (70 to 180 mg/mL [3.9 to 9.9 mmol/L]) over 14 days. A 14-day TIR > 70% is associated with decreased risk of diabetes complications and is inversely correlated with HbA1C level (7). To decrease risk of severe hypoglycemia, time below range (< 70 mg/dL [< 3.9 mmol/L]) should be < 4%, and time below 54 mg/L (< 3.0 mmol/L) should be < 1% (7, 8 ). As with all glycemic targets, CGM targets should be individualized depending on age, comorbidities, and risk of hypoglycemia.

CGM systems can be integrated with insulin pumps to provide real-time adjustment of insulin doses based on blood glucose levels. Such systems, known as automated insulin delivery (AID) systems or hybrid closed-loop systems, are expensive; however, they are recommended for all patients who take multiple daily injections of insulin and have been shown to lower HbA1C levels and decrease hypoglycemia (6, 9, 10). They are becoming more commonly used, and some versions do not require daily fingerstick glucose testing to calibrate the glucose monitor. They are especially useful in patients with type 1 diabetes and for those with hypoglycemia unawareness or nocturnal hypoglycemia. Some CGM sensors can be used for up to 2 weeks before they need to be replaced. Clinicians can review the recorded data to determine whether the patient is experiencing undetected hyperglycemia or hypoglycemia.

HbA1C levels reflect glucose control over the preceding 3 months and hence assess control between physician visits. HbA1C should be assessed quarterly in patients with type 1 diabetes and at least twice a year in patients with type 2 diabetes when plasma glucose appears stable and more frequently when control is uncertain. For most patients, the goal HbA1C is < 7%; however, this goal should be individualized. Home testing kits are available but are used infrequently.

Control suggested by HbA1C values sometimes appears to differ from that suggested by daily glucose readings because of falsely elevated or normal HbA1C values. False elevations of HbA1C may occur with low red blood cell turnover (as occurs with iron, folate, or vitamin B12 deficiency anemia), high-dose aspirin, and high blood alcohol concentrations. Falsely normal HbA1C values occur with increased red blood cell turnover, as occurs with hemolytic anemias and hemoglobinopathies (eg, HbS disease, HbC disease), or during treatment of deficiency anemias. In patients with cirrhosis or chronic kidney disease stages 4 and 5, correlation between HbA1C and glycemic levels is poor, and HbA1C can be falsely decreased in these patients. Pregnancy also falsely decreases HbA1C values.

Fructosamine, which is mostly glycosylated albumin but also comprises other glycosylated proteins, reflects glucose control in the previous 1 to 2 weeks. Fructosamine monitoring may be used during intensive treatment of diabetes and for patients with hemoglobin variants or high red blood cell turnover (which cause false HbA1C results), but it is mainly used in research settings.

Urine glucose monitoring is too inaccurate to be recommended. Self-measurement of urine ketones is recommended for patients with type 1 diabetes if they experience symptoms, signs, or triggers of ketoacidosis, such as nausea or vomiting, abdominal pain, fever, cold or flu-like symptoms, or unusual sustained hyperglycemia (> 250 to 300 mg/dL [> 13.9 to 16.7 mmol/L]) during glucose self-monitoring.

1. 1. Holt RIG, DeVries JH, Hess-Fischl A, et al: The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 44(11):2589–2625, 2021. doi: 10.2337/dci21-0043

2. 2. Domingo-Lopez DA, Lattanzi G, H J Schreiber L, et al. Medical devices, smart drug delivery, wearables and technology for the treatment of Diabetes Mellitus. Adv Drug Deliv Rev 2022;185:114280. doi:10.1016/j.addr.2022.114280

3. 3. Beck RW, Riddlesworth T, Ruedy K, et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. JAMA 2017;317(4):371-378. doi:10.1001/jama.2016.19975

4. 4. Olafsdottir AF, Polonsky W, Bolinder J, et al. A Randomized Clinical Trial of the Effect of Continuous Glucose Monitoring on Nocturnal Hypoglycemia, Daytime Hypoglycemia, Glycemic Variability, and Hypoglycemia Confidence in Persons with Type 1 Diabetes Treated with Multiple Daily Insulin Injections (GOLD-3). Diabetes Technol Ther 2018;20(4):274-284. doi:10.1089/dia.2017.0363

5. 5. Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM. Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care 2012;35(1):32-38. doi:10.2337/dc11-1438

6. 6. Grunberger G, Sherr J, Allende M, et al. American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus. Endocr Pract 2021;27(6):505-537. doi:10.1016/j.eprac.2021.04.008

7. 7. Battelino T, Danne T, Bergenstal RM, et al: Clinical targets for continuous glucose monitoring data interpretation: Recommendations from the international consensus on time in range. Diabetes Care 42(8):1593–1603, 2019. doi: 10.2337/dci19-0028.

8. 8. American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 46 (Supplement 1): 1-291, 2023.

9. 9. Brown SA, Kovatchev BP, Raghinaru D, et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J Med 2019;381(18):1707-1717. doi:10.1056/NEJMoa1907863

10. 10. Tauschmann M, Thabit H, Bally L, et alLancet 2018 Oct 13;392(10155):1310]. Lancet 2018;392(10155):1321-1329. doi:10.1016/S0140-6736(18)31947-0

The term brittle diabetes has been used to refer to patients who have dramatic, recurrent swings in glucose levels, often for no apparent reason. Labile plasma glucose levels are more likely to occur in patients with type 1 diabetes because endogenous insulin production is almost completely absent, and in some patients, counter-regulatory response to hypoglycemia is impaired. Other causes of labile plasma glucose levels include occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrine disorders (eg, Addison disease).

Patients with chronic difficulty maintaining acceptable glucose levels should be evaluated for situational factors that affect glucose control. Such factors include inadequate patient education or understanding that leads to errors in insulin administration, inappropriate food choices, and psychosocial stress that expresses itself in erratic patterns of medication use and food intake.

The initial approach is to thoroughly review self-care techniques, including insulin preparation and injection and glucose testing. Increased frequency of self-testing may reveal previously unrecognized patterns and provides the patient with helpful feedback. A thorough dietary history, including timing of meals, should be taken to identify potential contributions to poor control. Underlying disorders should be ruled out by physical examination and appropriate laboratory tests.

For some insulin-treated patients, changing to a more intensive regimen that allows for frequent dose adjustments (based on glucose testing) is helpful. Continuous glucose monitoring with alarms and sensor-augmented or hybrid closed-loop insulin pump therapy are useful tools in individuals who fluctuate between hypoglycemia and hyperglycemia.

Diabetes in children is discussed in more detail elsewhere.

Children with type 1 diabetes require physiologic insulin replacement as do adults, and similar treatment regimens, including , are used. However, the risk of hypoglycemia, because of unpredictable meal and activity patterns and limited ability to report hypoglycemic symptoms, may require modification of treatment goals. Most young children can be taught to actively participate in their own care, including glucose testing and insulin injections. School personnel and other caregivers must be informed about the disease and instructed about the detection and treatment of hypoglycemic episodes. Monitoring for microvascular complications can generally be deferred until after puberty.

Children with type 2 diabetes require the same attention to diet and weight control and recognition and management of dyslipidemia and hypertension as do adults. Most children with type 2 diabetes have obesity, so lifestyle modification is the cornerstone of therapy. Medication therapy may also be indicated.

Diabetes in adolescents is discussed in more detail elsewhere.

Glucose control typically deteriorates as children with diabetes enter adolescence. Multiple factors contribute, including

• Pubertal and insulin-induced weight gain

• Hormonal changes that decrease insulin sensitivity

• Psychosocial factors that lead to insulin nonadherence (eg, mood and anxiety disorders, hectic schedules, irregular meals, family conflict)

• Experimentation with cigarette, alcohol, and substance use

• Eating disorders that lead to insulin omission as a means of controlling weight

For these reasons, some adolescents experience recurrent episodes of hyperglycemia, diabetic ketoacidosis, and hypoglycemia requiring emergency department visits and hospitalization.

Treatment often involves intensive medical supervision combined with psychosocial interventions (eg, mentoring or support groups), individual or family therapy, and psychopharmacology when indicated. Patient education is important so that adolescents can safely enjoy the freedoms of early adulthood. Rather than judging personal choices and behaviors, clinicians must continually reinforce the need for careful glycemic control, especially frequent glucose monitoring and use of frequent, low-dose, fast-acting insulins as needed.

Diabetes mellitus may be a primary reason for hospitalization or may accompany other illnesses that require inpatient care. All patients with diabetic ketoacidosis, hyperosmolar hyperglycemic state, or prolonged or severe hypoglycemia should be hospitalized. Patients with hypoglycemia induced by sulfonylureas, poorly controlled hyperglycemia, or acute worsening of diabetic complications may benefit from brief hospitalization. Children and adolescents with new-onset diabetes may also benefit from hospitalization. Control may worsen on discharge when insulin regimens developed in controlled inpatient settings prove inadequate to the uncontrolled conditions outside the hospital. In patients with newly diagnosed diabetes, insulin doses used in the inpatient setting are often too high and can cause hypoglycemia if not adjusted when discharged from the hospital.

When other illnesses mandate hospitalization, some patients can continue on their home diabetes treatment regimens. However, glucose control often proves difficult, and it is often neglected when other diseases are more acute. Restricted physical activity and acute illness worsen hyperglycemia in some patients, whereas dietary restrictions and symptoms that accompany illness (eg, nausea, vomiting, diarrhea, anorexia) precipitate hypoglycemia in others—especially when antihyperglycemic medication doses remain unchanged. In addition, it may be difficult to control glucose adequately in patients who are hospitalized because usual routines (eg, timing of meals, medications, and procedures) are inflexibly timed relative to diabetes treatment regimens.

lactic acidosis

Most inpatients can be appropriately treated with basal insulin without or with supplemental short-acting insulin. Dipeptidyl peptidase-4 inhibitors are relatively safe, even in patients with kidney disease, and they may also be used for postprandial glucose lowering.

Sliding-scale insulininsulins should be adjusted to prevent hyperglycemia rather than just using short-acting insulins to correct it.

Inpatient hyperglycemia is associated with increased infection rate and mortality. Critical illness causes insulin resistance and hyperglycemia even in patients without known diabetes mellitus. Such stress-induced hyperglycemia is associated with poor outcomes, including increased mortality. Insulin infusion to maintain plasma glucose between 140 and 180 mg/dL (7.8 and 10.0 mmol/L)

• Prevents adverse outcomes such as organ failure

• Possibly enhances recovery from stroke

• Leads to improved survival in patients requiring prolonged (> 5 days) critical care

Previously, glucose target levels were lower; however, it appears that the less stringent targets as described above may be sufficient to prevent adverse outcomes. Severely ill patients, especially those treated with glucocorticoids or pressors and those receiving total parenteral nutrition (TPN), may need very high doses of insulin (> 5 to 10 units/hour) because of insulin resistance. In critically ill patients or postsurgical patients who are in an intensive care unit, insulin infusion protocols and/or computerized algorithms can be used to titrate insulin drips to maintain euglycemia.

The physiologic stress of surgery can increase plasma glucose in patients with diabetes and induce diabetic ketoacidosis in those with type 1 diabetes. For shorter procedures, subcutaneous insulin can be used. In patients with type 1 diabetes, one half to two thirds of the usual morning dose of intermediate-acting insulin or 70 to 80% of the dose of long-acting insulin (glargine or detemir) can be given the night or morning before surgery (at the usual time of long-acting insulin administration).

Patients with type 2 diabetes who are taking insulin should be given 50% of their basal insulin

insulin can be given subcutaneously every 4 to 6 hours as needed to maintain the plasma glucose level between 100 and 200 mg/dL (5.5 and 11.1 mmol/L) until the patient can be switched to oral feedings and resume the usual insulin regimen. Additional doses of intermediate- or long-acting insulin should be given if there is a substantial delay (> 24 hours) in resuming the usual regimen. This approach may also be used for insulin-treated patients with type 2 diabetes, but frequent measurement of ketones may be omitted.

Some physicians prefer to withhold subcutaneous or inhaled insulin on the day of surgery and to give insulin by IV infusion. For patients undergoing a long procedure or major surgery, a continuous insulin infusion is preferable, especially since insulin requirements can increase because of the stress of surgery. IV insulin infusion can be given at the same time as intravenous dextrose solution to maintain blood glucose. One approach is to combine glucose, insulin, and potassium in the same bag (GIK regimen), for example, by combining 10% dextrose with 10 mEq (10 mmol) potassium, and 15 units of insulin in a 500-mL bag. The insulin doses are adjusted in 5-unit increments. This approach is not used at many institutions because of the frequent remixing and changing of bags needed to adjust to the patient's level of glycemia. A more common approach in the United States is to infuse insulinInsulininsulin rate may need to be decreased for patients with more insulin-sensitive type 1 diabetes and increased for patients with more insulin-resistant type 2 diabetes. Ten percent dextrose may also be used. It is important, especially in patients with type 1 diabetes, to continue insulin infusion to avoid development of diabetes ketoacidosis. Insulin adsorption onto IV tubing can lead to inconsistent effects, which can be minimized by preflushing the IV tubing with insulin solution. Insulin infusion is continued through recovery, with insulin dose adjusted based on the plasma glucose levels obtained in the recovery room and at 1- to 2-hour intervals thereafter.

Most patients with type 2 diabetes who are treated only with oral antihyperglycemic medications maintain acceptable glucose levels when fasting and may not require insulin

People at high risk of type 1 diabetes (eg, siblings and children of people with type 1 diabetes) can be tested for the presence of islet cell or anti-glutamic acid decarboxylase antibodies, which precede onset of clinical disease (1).

Risk factors for type 2 diabetes include

• Age ≥ 35 years

• Overweight or obesity

• Sedentary lifestyle

• Family history of type 2 diabetes mellitus

• History of impaired glucose regulation (prediabetes)

• Gestational diabetes mellitus or delivery of a baby > 4.1 kg

• Hypertension

• Dyslipidemia (high-density lipoprotein [HDL] cholesterol < 35 mg/dL [0.9 mmol/L] or triglyceride level > 250 mg/dL [2.8 mmol/L])

• History of cardiovascular disease

• Polycystic ovary syndrome

• African, Hispanic, Asian, or American Indian ancestry

• Steatotic liver disease (formerly fatty liver disease)

• HIV infection

People ≥ age 35 years and all adults with the additional risk factors described above should be screened for diabetes with an FPG level, HbA1C, or a 2-hour value on a 75-g OGTT at least once every 3 years as long as plasma glucose measurements are normal and at least annually if results reveal impaired fasting glucose levels (see table Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation).

1. 1. Sims EK, Besser REJ, Dayan C, et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective. Diabetes 2022;71(4):610-623. doi:10.2337/dbi20-0054

There are no current therapies to completely prevent type 1 diabetes.

≥ 2 autoantibodies and elevated glucose without symptoms) who had a relative with type 1 diabetes (n = 76), the use of teplizumab (14-day course) versus placebo resulted in a median 24-month delay in time to diagnosis of type 1 diabetes in the initial trial (1) and 33 months in a follow-up study (2). In addition, in the follow-up study, after a median of 923 days, stage 3 type 1 diabetes was diagnosed at lower rates in participants treated with teplizumab versus placebo (22% vs. 50%).

3).

3, 45).

Patients with impaired glucose regulation should receive counseling addressing their risk of developing diabetes and the importance of lifestyle changes for preventing diabetes. They should be monitored closely for development of diabetes symptoms or elevated plasma glucose. Ideal follow-up intervals have not been determined, but annual or biannual checks are probably appropriate.

Type 2 diabetes usually can be prevented with lifestyle modification. Weight loss of as little as 7% of baseline body weight, combined with moderate-intensity physical activity (eg, walking 30 minutes/day), may reduce the incidence of diabetes in high-risk people by > 50% (6).

Metformin is safe and cost-effective and has the strongest evidence for the prevention of diabetes. It can be considered if diet and lifestyle are not successful, especially in patients who are at highest risk for developing diabetes (body mass index ≥ 35 or history of gestational diabetes) (7, 8).

In patients with obesity, pharmacotherapy for weight loss, medical devices, and weight loss surgery can be used as adjuncts to diet and physical activity (see weight loss in diabetes). Metabolic surgery (bariatric surgery) has been shown to decrease the risk of progression to diabetes (9).

Risk of complications of diabetes can be decreased by strict control of plasma glucose, defined as HbA1C < 7%, and by control of hypertension and lipid levels. For most patients with diabetes, blood pressure should be maintained at < 130/80 mm Hg, although blood pressure targets may need to be individualized with consideration of adverse effects of antihypertensive medications. Specific measures for prevention of progression of complications once detected are described under Complications and Treatment.

1. 1. Herold KC, Bundy BN, Long SA, et al. An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes [published correction appears in N Engl J Med 2020 Feb 6;382(6):586]. N Engl J Med 2019;381(7):603-613. doi:10.1056/NEJMoa1902226

2. 2. Sims EK, Bundy BN, Stier K, et al. Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Sci Transl Med 2021;13(583):eabc8980. doi:10.1126/scitranslmed.abc8980

3. 3. Martin S, Schernthaner G, Nerup J, et al. Follow-up of cyclosporin A treatment in type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects. Diabetologia 1991;34(6):429-434. doi:10.1007/BF00403182

4. 4. Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022;13(10):835-850. doi:10.4239/wjd.v13.i10.835

5. 5. Forlenza GP, McVean J, Beck RW, et al. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA 2023;329(12):990-999. doi:10.1001/jama.2023.2064

6. 6. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346(6):393-403. doi:10.1056/NEJMoa012512

7. 7. Hostalek U, Gwilt M, Hildemann S. Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention. Drugs 2015;75(10):1071-1094. doi:10.1007/s40265-015-0416-8

8. 8. American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 46 (Supplement 1): 1-291, 2023.

9. 9. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351(26):2683-2693. doi:10.1056/NEJMoa035622