3101 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology CHAPTER 403

of pathophysiologic mechanisms contribute to type 2 DM and their

relative importance varies from individual to individual. As insulin

resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state, manifesting as IGT, defined as elevations in postprandial

glucose. A decline in insulin secretion and/or increased glucagon

secretion causes an increase in hepatic glucose production leading to

fasting hyperglycemia. Ultimately, frank beta cell failure ensues as a

combination of these mechanisms leading to the manifestation of type

2 diabetes.

Metabolic Abnormalities Insulin resistance, the decreased ability

of insulin to act effectively on target tissues (especially muscle, liver,

and fat), is a prominent feature of type 2 DM and results from a combination of genetic susceptibility, obesity, and metabolic inflammation.

Insulin resistance is relative, however, because supranormal levels of

circulating insulin will normalize the plasma glucose. In type 2 DM,

both insulin potency and efficacy are reduced leading to an overall

decrease in glucose utilization under many conditions (30–60% lower

than in normal individuals). Insulin resistance impairs glucose utilization by insulin-sensitive tissues (skeletal muscle) and in liver, coupled

with elevated glucagon, leads to increased hepatic glucose output.

Increased hepatic glucose output predominantly accounts for increased

FPG levels, whereas decreased peripheral glucose utilization results in

postprandial hyperglycemia.

The precise molecular mechanism leading to insulin resistance in

type 2 DM has not been elucidated. Insulin receptor levels and tyrosine

kinase activity in skeletal muscle are reduced, but these alterations are

most likely secondary to hyperinsulinemia and are not a primary

defect. Therefore, “postreceptor” defects in insulin-regulated phosphorylation/dephosphorylation appear to play the predominant role

in insulin resistance. Abnormalities include the accumulation of lipid

intermediates within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production. Impaired fatty acid oxidation and lipid

accumulation within skeletal myocytes also may generate reactive

oxygen species such as lipid peroxides. These and other mechanisms

also generate low-grade metabolic inflammation that feeds back and

directly worsens insulin resistance. Of note, not all insulin signal

transduction pathways are resistant to the effects of insulin (e.g.,

those controlling cell growth and differentiation using the mitogenicactivated protein kinase pathway). Consequently, hyperinsulinemia may increase the insulin action through these pathways, potentially accelerating diabetes-related conditions such as

atherosclerosis.

The obesity accompanying type 2 DM, particularly in a central

or visceral location, is thought to be part of the pathogenic process

(Chap. 401). In addition to these white fat depots, humans have brown

fat, which has much greater thermogenic capacity. Efforts are underway to increase the activity or quantity of brown fat. The increased

adipocyte mass leads to increased levels of circulating free fatty acids

and other fat cell products. For example, adipocytes secrete a number

of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-α, resistin, IL-6, and adiponectin). Further, adipose

resident macrophages are an important source of metabolic inflammation in diabetes. In addition to regulating body weight, appetite,

and energy expenditure, adipokines also modulate insulin sensitivity.

The increased production of free fatty acids and some adipokines

may cause insulin resistance in skeletal muscle and liver. The venous

drainage of the visceral adipose beds is the portal circulation and this

likely contributes to hepatic dysfunction. Free fatty acids also impair

glucose utilization in skeletal muscle, promote glucose production by

the liver, and impair beta cell function. In contrast, the production by

adipocytes of adiponectin, an insulin-sensitizing peptide, is reduced in

obesity, and this may contribute to hepatic insulin resistance. Adipocyte products and adipokines also produce an inflammatory state and

may explain why markers of inflammation such as IL-6 and C-reactive

protein are often elevated in type 2 DM.

IMPAIRED INSULIN SECRETION Insulin secretion and sensitivity are

interrelated (Fig. 403-7). In type 2 DM, insulin secretion initially

increases in response to insulin resistance to maintain normal glucose

tolerance. Initially, the insulin secretory defect is mild and selectively

involves glucose-stimulated insulin secretion, including a greatly

reduced first secretory phase. The response to other nonglucose secretagogues, such as arginine, is preserved, but overall beta cell function

is reduced by as much as 50% at the onset of type 2 DM. Abnormalities in proinsulin processing are reflected by increased secretion of

proinsulin in type 2 DM. Eventually, the insulin secretory defect is

progressive.

The reason(s) for the decline in insulin secretory capacity in type

2 DM is unclear. The assumption is that a second genetic defect—

superimposed upon insulin resistance—leads to defects in beta cell

function, mass, and potentially cellular identity and differentiation

status. Islet amyloid polypeptide or amylin, co-secreted by the beta cell,

forms amyloid fibrillar deposits found in the islets of individuals with

long-standing type 2 DM. Whether such islet amyloid deposits are a

primary or secondary event is not known. The metabolic environment

of diabetes also negatively impacts islet function. For example, chronic

hyperglycemia paradoxically impairs islet function (“glucose toxicity”)

and leads to a worsening of hyperglycemia. Improvement in glycemic

control is often associated with improved islet function, an important

clinical consideration. In addition, elevated levels of free fatty acids

(“lipotoxicity”), and systemic and local elevations in pro-inflammatory

cytokines from increased numbers of islet-associated macrophages,

may also worsen islet function.

INCREASED HEPATIC GLUCOSE AND LIPID PRODUCTION In type 2

DM, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis, which results in fasting hyperglycemia and decreased glycogen storage by the liver in the postprandial

state. Increased hepatic glucose production occurs early in the course

of diabetes, although likely after the onset of insulin and glucagon

secretory abnormalities and insulin resistance in skeletal muscle. As

a result of insulin resistance in adipose tissue, lipolysis and free fatty

acid flux from adipocytes are increased and efficiently cleared by liver

leading to increased very-low-density lipoprotein (VLDL)-triglyceride

synthesis in hepatocytes and secretion from liver. This is also responsible for the dyslipidemia found in type 2 DM (elevated triglycerides,

reduced high-density lipoprotein [HDL], and increased small dense

low-density lipoprotein [LDL] particles). If this lipid is retained,

steatosis in the liver may lead to nonalcoholic fatty liver disease and

abnormal liver function tests.

Insulin Resistance Syndromes The insulin resistance condition

comprises a spectrum of disorders, with hyperglycemia representing

one of the most readily diagnosed features. The metabolic syndrome,

the insulin resistance syndrome, and syndrome X are terms used to

describe a constellation of metabolic derangements that includes

insulin resistance, hypertension, dyslipidemia (decreased HDL and elevated triglycerides), central or visceral obesity, type 2 DM or IGT/IFG,

and accelerated cardiovascular disease. This syndrome is discussed in

Chap. 408.

A number of relatively rare forms of severe insulin resistance

include features of type 2 DM or IGT (Table 403-1). Mutations in the

insulin receptor that interfere with binding or signal transduction are

a rare cause of insulin resistance. Acanthosis nigricans and signs of

hyperandrogenism (hirsutism, acne, and oligomenorrhea in women)

are also common physical features. Two distinct syndromes of severe

insulin resistance have been described in adults: (1) type A, which

affects young women more severely and is characterized by severe

hyperinsulinemia, obesity, and features of hyperandrogenism; and

(2) type B, which affects middle-aged women and is characterized by

severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders. Individuals with type A insulin resistance syndrome

have an undefined defect in the insulin-signaling pathway; individuals

with type B insulin resistance syndrome have autoantibodies directed

3102 PART 12 Endocrinology and Metabolism

at the insulin receptor. These receptor autoantibodies may block insulin binding or may stimulate the insulin receptor, leading to intermittent hypoglycemia.

Polycystic ovary syndrome (PCOS) is a common disorder that

affects premenopausal women and is characterized by chronic anovulation and hyperandrogenism (Chap. 392). Insulin resistance is seen

in a significant subset of women with PCOS, and the disorder substantially increases the risk for type 2 DM, independent of the effects

of obesity.

Lipodystrophies are a group of heterogeneous disorders characterized by selective loss of adipose tissue, leading to severe insulin

resistance and hypertriglyceridemia. Lipodystrophies can be inherited

or acquired and associated with variable degrees of adipose tissue loss.

Prevention Type 2 DM is preceded by a period of IGT or IFG, and

a number of lifestyle modifications and pharmacologic agents prevent

or delay the onset of DM. Individuals with prediabetes or increased

risk of diabetes should be referred to a structured program to reduce

body weight and increase physical activity as well as being screened

for cardiovascular disease. The Diabetes Prevention Program (DPP)

demonstrated that intensive changes in lifestyle (diet and exercise

for 30 min/d five times/week) in individuals with IGT prevented or

delayed the development of type 2 DM by 58% compared to placebo.

This effect was seen in individuals regardless of age, sex, or ethnic

group. In the same study, metformin prevented or delayed diabetes by

31% compared to placebo. The lifestyle intervention group lost 5–7%

of their body weight during the 3 years of the study; the effects of the

intervention persisted for at least 15 years. Studies in Finnish and Chinese populations noted similar efficacy of diet and exercise in preventing or delaying type 2 DM. A number of agents, including α-glucosidase

inhibitors, metformin, thiazolidinediones, GLP-1 receptor pathway

modifiers, SGLT-2 inhibitors, and orlistat, prevent or delay type 2 DM

but are not approved by the U.S. Food and Drug Administration for

this purpose. Individuals with a strong family history of type 2 DM and

individuals with IFG or IGT should be strongly encouraged to achieve

a normal BMI and engage in regular physical activity. Pharmacologic

therapy for individuals with prediabetes is currently controversial

because its cost-effectiveness and safety profile are not known. The ADA

suggests that metformin be considered in individuals with both IFG and

IGT who are at very high risk for progression to diabetes (age <60 years,

BMI ≥35 kg/m2

, and women with a history of GDM). Individuals with

IFG, IGT, or an HbA1c of 5.7–6.4% should be monitored annually to

determine if diagnostic criteria for diabetes are present.

GENETICALLY DEFINED, MONOGENIC

FORMS OF DM RELATED TO REDUCED

INSULIN SECRETION

Several monogenic forms of DM have been identified. Cases of maturity-onset diabetes of the young (MODY) or monogenic diabetes are

caused by mutations in genes encoding islet-enriched transcription

factors or glucokinase (Fig. 403-5; Table 403-1) and present with an

autosomal dominant mode of transmission. MODY 1, MODY 3, and

MODY 5 are caused by mutations in hepatocyte nuclear transcription

factor (HNF) 4α, HNF-1α, and HNF-1β, respectively. As their names

imply, these transcription factors are expressed in the liver but also

in other tissues, including the pancreatic islets and kidney. These

factors most likely affect islet development, the expression of genes

important in glucose-stimulated insulin secretion or the maintenance

of beta cell mass. For example, individuals with an HNF-1α mutation

(MODY 3) have a progressive decline in glycemic control but may

respond to sulfonylureas. In fact, some of these patients were initially

thought to have type 1 DM but were later shown to respond to a sulfonylurea, and insulin was discontinued, a major clinical implication.

Individuals with an HNF-1β mutation have progressive impairment

of insulin secretion and hepatic insulin resistance, and require insulin

treatment with minimal response to sulfonylureas. These individuals

often have other abnormalities such as renal cysts, mild pancreatic

exocrine insufficiency, and abnormal liver function tests. Individuals

with MODY 2, the result of mutations in the glucokinase gene, have

mild-to-moderate, but stable hyperglycemia that does not respond to

oral hypoglycemic agents, and otherwise does not require treatment.

Glucokinase catalyzes the formation of glucose-6-phosphate from

glucose, a reaction that is important for glucose sensing by the beta

cells (Fig. 403-5) and for glucose utilization by the liver. As a result

of glucokinase mutations, higher glucose levels are required to elicit

insulin secretory responses, thus altering the set point for insulin secretion. MODY 4 is a rare variant caused by mutations in pancreatic and

duodenal homeobox 1, a transcription factor that regulates pancreatic

development and insulin gene transcription. Homozygous inactivating

mutations cause pancreatic agenesis, whereas heterozygous mutations

may result in DM. Studies of populations with type 2 DM suggest that

mutations in MODY-associated genes are an uncommon (<5%) cause

of type 2 DM.

Transient or permanent neonatal diabetes (onset <6 months of age)

occurs. Permanent neonatal diabetes is a heterogeneous group of disorders caused by genetic mutations that impact beta cell function and/

or pancreatic development (Fig. 403-5). Affected individuals typically

require treatment with insulin and exhibit phenotypic overlap with

type 1 DM. Activating mutations in the ATP-sensitive potassium channel subunits (Kir6.2 and ABCC8) impair glucose-stimulated insulin

secretion. However, these individuals may respond to sulfonylureas

and can be treated with these agents. Mutations in the transcription

factor GATA6 are the most common cause of pancreatic agenesis.

Homozygous glucokinase mutations cause a severe form of neonatal

diabetes, while mutations in mitochondrial DNA are associated with

diabetes and deafness. A number of mutations identified in the coding

sequence of the insulin gene have been found to interfere with proinsulin folding, processing, and bioactivity and are designated as Mutant

Ins-gene-induced Diabetes of Youth (MIDYs). Some of the neonatal

diabetes syndromes are associated with a spectrum of neurologic

dysfunction and a variety of extrapancreatic manifestations. Any individual who developed diabetes at 6 months of age or who has atypical

features of type 1 or type 2 diabetes should be screened for forms of

monogenic diabetes.

APPROACH TO THE PATIENT

Diabetes Mellitus

Once the diagnosis of DM is made, attention should be directed to

symptoms related to diabetes (acute and chronic) and classifying

the type of diabetes. DM and its complications produce a wide

range of symptoms and signs; those secondary to acute hyperglycemia may occur at any stage of the disease, whereas those related to

chronic hyperglycemia typically begin to appear during the second

decade of hyperglycemia (Chap. 405). Because of long delays in

clinical recognition, individuals with previously undetected type 2

DM may present with chronic complications of DM at the time of

diagnosis. The history and physical examination should assess for

symptoms or signs of acute hyperglycemia and screen for chronic

microvascular and macrovascular complications and conditions

associated with DM (Chap. 405).

HISTORY

A complete medical history should be obtained with special emphasis on DM-relevant aspects such as current weight as well as any

recent changes in weight, family history of DM and its complications, sleep history, risk factors for cardiovascular disease, exercise,

smoking status, history of pancreatic disease, and ethanol use.

Symptoms of hyperglycemia include polyuria, polydipsia, weight

loss, fatigue, weakness, blurry vision, frequent superficial infections (vaginitis, fungal skin infections), and slow healing of skin

lesions after minor trauma. Metabolic derangements relate mostly

to hyperglycemia (osmotic diuresis) and to the catabolic state of the

patient (urinary loss of glucose and calories, muscle breakdown due

3103 Diabetes Mellitus: Diagnosis, Classification, and Pathophysiology CHAPTER 403

to protein degradation and decreased protein synthesis). Blurred

vision results from changes in the water content of the lens and

resolves as hyperglycemia is controlled.

In a patient with established DM, the initial assessment should

include a review of symptoms at the time of the initial diabetes

diagnosis. This is an essential part of the history that can help

define whether the correct type of DM has been diagnosed. Special

emphasis should be placed on prior diabetes care, including types of

therapies tried, the nature of any intolerance to previous therapies,

prior HbA1c levels, self-monitoring blood glucose results, frequency

of hypoglycemia (<3.0 mmol/L, <54 mg/dL), presence of DM-specific complications, and assessment of the patient’s knowledge about

diabetes, exercise, nutrition, and sleep history. Diabetes-related

complications may afflict several organ systems, and an individual

patient may exhibit some, all, or none of the symptoms related to

the complications of DM (Chap. 405). In addition, the presence of

DM-related comorbidities should be established (cardiovascular

disease, hypertension, dyslipidemia). Pregnancy plans should be

ascertained in women of childbearing age. The American Diabetes

Association recommends that all women of childbearing age be

counseled about the importance of tight glycemic control (HbA1c

<6.5%) prior to conception.

PHYSICAL EXAMINATION

In addition to a complete physical examination, special attention

should be given to DM-relevant aspects such as weight and BMI,

retinal examination, orthostatic blood pressure, foot examination,

peripheral pulses, and insulin injection sites. Depending on other

risk factors, a blood pressure >130/80 mmHg or >140/90 mmHg

is considered hypertension in individuals with diabetes. Because

periodontal disease is more frequent in DM, the teeth and gums

should also be examined.

An annual foot examination should (1) assess blood flow (pedal

pulses), sensation (vibratory sensation [128-MHz tuning fork at the

base of the great toe], the ability to sense touch with a monofilament

[5.07, 10-g monofilament]), pinprick sensation, ankle reflexes, and

nail care; (2) look for the presence of foot deformities such as hammer or claw toes and Charcot foot; and (3) identify sites of potential ulceration. The ADA recommends annual screening for distal

symmetric polyneuropathy beginning with the initial diagnosis of

diabetes and annual screening for autonomic neuropathy 5 years

after diagnosis of type 1 DM and at the time of diagnosis of type 2

DM. This testing is aimed at detecting loss of protective sensation

(LOPS) caused by diabetic neuropathy (Chap. 405).

CLASSIFICATION OF DM IN AN INDIVIDUAL PATIENT

The etiology of diabetes in an individual with new-onset disease can

usually be assigned on the basis of clinical criteria. Individuals with

type 1 DM are more likely to have the following characteristics: (1)

lean body habitus; (2) requirement of insulin as the initial therapy;

(3) propensity to develop ketoacidosis; and (4) a family or personal

history of other autoimmune disorders such as autoimmune thyroid

disease, adrenal insufficiency, pernicious anemia, celiac disease,

and vitiligo. In contrast, individuals with type 2 DM often exhibit

the following features: (1) obesity; 80% are obese, but elderly individuals may be lean; (2) may not require insulin therapy initially;

and (3) may have associated conditions such as insulin resistance,

hypertension, cardiovascular disease, dyslipidemia, or polycystic

ovarian syndrome. In type 2 DM, insulin resistance is often associated with abdominal obesity (as opposed to hip and thigh obesity)

and hypertriglyceridemia. Although most individuals diagnosed

with type 2 DM are older, the age of diagnosis is declining, and

there is a marked increase among overweight children and adolescents. Some individuals with phenotypic type 2 DM present with

diabetic ketoacidosis but lack autoimmune markers and may be

later treated with oral glucose-lowering agents rather than insulin

(this clinical picture is sometimes referred to as ketosis-prone type

2 DM). On the other hand, some individuals (5–10%) with the

phenotypic appearance of type 2 DM do not have absolute insulin

deficiency but have autoimmune markers (GAD and other ICA

autoantibodies) suggestive of type 1 DM (sometimes termed latent

autoimmune diabetes of the adult). Such individuals are more likely

to require insulin treatment within 5 years. Monogenic forms of

diabetes should be considered in those with diabetes onset in childhood or early adulthood and especially those diagnosed within the

first 6 months of life, an autosomal pattern of diabetes inheritance,

diabetes without typical features of type 1 or 2 diabetes, and stable

mild fasting hyperglycemia. Genetic testing should be considered

in individuals suspected of having a monogenic form of diabetes

as this may guide therapy selection. Despite recent advances in

the understanding of the pathogenesis of diabetes, it often remains

difficult to categorize some patients unequivocally. Individuals who

deviate from the clinical profile of type 1 and type 2 DM, or who

have other associated defects such as deafness, pancreatic exocrine

disease (type 3c DM), and other endocrine disorders, should be

classified accordingly (Table 403-1). A major goal is personalized

or precision medicine in the diagnosis and treatment of diabetes.

LABORATORY ASSESSMENT

The laboratory assessment should first determine whether the

patient meets the diagnostic criteria for DM (Fig. 403-1) and then

assess the degree of glycemic control (Chap. 404). In addition to the

standard laboratory evaluation, the patient should be screened for

DM-associated conditions (e.g., albuminuria, dyslipidemia, thyroid

dysfunction).

The classification of the type of DM may be facilitated by laboratory assessments. Serum C-peptide measurements may be useful but

should always be interpreted with a concurrent blood glucose level.

A low C-peptide in the setting of an elevated blood glucose level

may confirm a patient’s need for insulin. However, C-peptide levels

are unable to completely distinguish type 1 from type 2 DM as many

individuals with type 1 DM retain some C-peptide production. Measurement of islet cell antibodies at the time of diabetes onset may

be useful if the type of DM is not clear based on the characteristics

described above.

■ FURTHER READING

Chung WK et al: Precision medicine in diabetes: A Consensus Report

from the American Diabetes Association (ADA) and the European

Association for the Study of Diabetes (EASD). Diabetologia 63:1671,

2020.

Classification and Diagnosis of Diabetes: Diabetes Care 44:S15,

2021.

Cole JB, Florez JC: Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 16:377, 2020.

Dimeglio LA et al: Type 1 diabetes. Lancet 391:2449, 2018.

Hill-Briggs F et al: Social determinants of health and diabetes: A

scientific review. Diabetes Care 44:258, 2021.

Insel RA et al: Staging presymptomatic type 1 diabetes: A scientific

statement of JDRF, the Endocrine Society, and the American Diabetes

Association. Diabetes Care 38:1964, 2015.

Powers AC: Type 1 diabetes mellitus: Much progress, many opportunities. J Clin Invest 131:142242, 2021.

Selph S et al: Screening for type 2 diabetes mellitus: A systematic

review for the U.S. Preventive Services Task Force. Ann Intern Med

162:765, 2015.

Skyler JS et al: Differentiation of diabetes by pathophysiology, natural

history, and prognosis. Diabetes 66:241, 2017.

Zhang H et al: Monogenic diabetes: a gateway to precision medicine

in diabetes. J Clin Invest 131:e142244, 2021.

3104 PART 12 Endocrinology and Metabolism

OVERALL GOALS

The goals of therapy for type 1 or type 2 diabetes mellitus (DM) are to

(1) eliminate symptoms related to hyperglycemia, (2) reduce or eliminate

the long-term microvascular and macrovascular complications of DM

(Chap. 405), and (3) allow the patient to achieve as normal a lifestyle as

possible. To reach these goals, the physician should identify a target level

of glycemic control for each patient, provide the patient with the educational and pharmacologic resources necessary to reach this level, and

monitor/treat DM-related complications. Symptoms of diabetes usually

resolve when the plasma glucose is <11.1 mmol/L (200 mg/dL), and thus

most DM treatment focuses on achieving the second and third goals.

This chapter first reviews the ongoing treatment of diabetes in the outpatient setting and then discusses the treatment of severe hyperglycemia, as

well as the treatment of diabetes in hospitalized patients.

The care of an individual with either type 1 or type 2 DM requires

a multidisciplinary team. Central to the success of this team are the

patient’s participation, input, and enthusiasm, all of which are essential

for optimal diabetes management. Members of the health care team

usually include the primary care provider and/or the endocrinologist

or diabetologist, a certified diabetes educator, a nutritionist, a psychologist, and possibly a social worker. In addition, when the complications

of DM arise, subspecialists (including ophthalmologists, neurologists,

podiatrists, nephrologists, cardiologists, and cardiovascular surgeons)

with experience in DM-related complications are essential.

ONGOING ASPECTS OF COMPREHENSIVE

DIABETES CARE

A number of names are sometimes applied to different approaches

to diabetes care, such as intensive insulin therapy, intensive glycemic

control, and “tight control.” The current chapter, and other sources,

uses the term comprehensive diabetes care to emphasize the fact that

optimal diabetes therapy involves more than glucose management and

medications and is patient-centered and individualized as advocated by

the American Diabetes Association (ADA). Although glycemic control

is central to optimal diabetes therapy, comprehensive diabetes care of

both type 1 and type 2 DM should also detect and manage DM-specific

complications (Chap. 405), and modify risk factors for DM-associated

diseases. The key elements of comprehensive diabetes care are summarized in Table 404-1. The morbidity and mortality of DM can be greatly

reduced by timely and consistent surveillance, including the detection,

prevention, and management of DM-related complications (Table

404-1 and Chap. 405). Such screening procedures are indicated for all

individuals with DM, but many individuals with diabetes do not receive

these or comprehensive diabetes care. In addition to the physical

aspects of DM, social, family, financial, cultural, and employment-related issues may impact diabetes care. The treatment goals for patients

with diabetes summarized in Table 404-2 should be individualized.

The prevention and treatment of clinically significant hypoglycemia

(<3.0 mmol/L or 54 mg/dL) is discussed in Chap. 406. This chapter,

while recognizing that resources available for diabetes care vary widely

throughout the world, provides guidance for comprehensive diabetes

care in health care settings with considerable societal resources.

Lifestyle Management in Diabetes Care The patient with

type 1 or type 2 DM should receive education about nutrition, physical activity, psychosocial support, care of diabetes during illness, and

medications to lower the plasma glucose. Patient education allows and

encourages individuals with DM to assume greater responsibility for

their care, leading to improved compliance.

404 Diabetes Mellitus:

Management and Therapies

Alvin C. Powers, Michael J. Fowler,

Michael R. Rickels

TABLE 404-1 Guidelines for Ongoing, Comprehensive Medical Care for

Individuals with Diabetes

• Individualized glycemic goal and therapeutic plan

• Self-monitoring at individualized frequency of blood glucose (capillary/meter)

or interstitial glucose (continuous glucose monitoring)

• HbA1c testing (2–4 times/year)

• Lifestyle management in the care of diabetes, including:

• Diabetes self-management education and support

• Nutrition therapy

• Physical activity

• Psychosocial care, including evaluation for depression, anxiety

• Detection, prevention, or management of diabetes-related complications,

including:

• Diabetes-related eye examination (annual or biannual; Chap. 405)

• Diabetes-related foot examination (1–2 times/year by provider; daily by

patient; Chap. 403)

• Diabetes-related neuropathy examination (annual; Chap. 403)

• Diabetes-related kidney disease testing (annual; Chap. 405)

• Manage or treat diabetes-relevant conditions, including:

• Blood pressure (assess 2–4 times/year; Chap. 405)

• Lipids (1–2 times/year; Chap. 405)

• Consider antiplatelet therapy with low-dose aspirin (Chap. 405)

• Influenza/pneumococcal/hepatitis B/coronavirus immunizations (Chap. 6)

Abbreviation: HbA1c, glycosylated hemoglobin A1c.

TABLE 404-2 Treatment Goals for Adults with Diabetesa

INDEX OF GLYCEMIC

CONTROLb

GOAL (NONPREGNANT

ADULTS)

GOAL (OLDER/HIGH-RISK

ADULTS)

HbA1c <7.0% (53 mmol/mol)c <8.0% (64 mmol/mol)c

Preprandial capillary

blood glucose

4.4–7.2 mmol/L

(80–130 mg/dL)

5.0–7.8 mmol/L (90–140

mg/dL)

Postprandial capillary

blood glucosed

Time in range

3.9–10.0 mmol/L

(70–180 mg/dL)e

Time below 3.9 mmol/L

(70 mg/dL)e

Glucose variability, %

coefficient of variatione

<10.0 mmol/L

(<180 mg/dL)

>70%

<4%

≤36%

<11.1 mmol/L (200 mg/dL)

>50%

<1%

<33%

a

As recommended by the American Diabetes Association; goals should be

individualized for each patient (see text) with personalized goals for different

patients. b

HbA1c is primary goal and may also be estimated from 14 or more days

of continuous glucose monitoring (CGM) data as the Glycemic Management

Indicator (GMI). c

Diabetes Control and Complications Trial-based assay. d

1–2 h after

beginning of a meal. e

Derived from 14 days of CGM data.

Abbreviation: HbA1c, glycosylated hemoglobin A1c.

Source: Data from American Diabetes Association: 6. Glycemic targets: Standards of

medical care in diabetes-2021. Diabetes Care 44(Suppl 1):S73, 2021.

Diabetes Self-Management Education and Support (DSMES)

DSMES refers to ways to improve the patient’s knowledge, skills, and

abilities necessary for diabetes self-care and should also emphasize

psychosocial issues and emotional well-being. Patient education is

a continuing process with regular visits for reinforcement; it is not

a process completed after one or two visits. It should receive special

emphasis at the diagnosis of diabetes, annually, or at times when

diabetes treatment goals are not attained, and during transitions in

life or medical care. DSMES is delivered by a diabetes educator who

is a health care professional (nurse, dietician, or pharmacist) with

specialized patient-education skills and who is certified in diabetes

education (e.g., Association of Diabetes Care & Education Specialists).

Education topics important for optimal diabetes self-care include selfmonitoring of blood glucose (SMBG) and/or continuous glucose monitoring (CGM); urine or blood ketone monitoring (type 1 DM); insulin

administration; guidelines for diabetes management during illnesses;

3105 Diabetes Mellitus: Management and Therapies CHAPTER 404

intake. An important component of MNT in type 1 DM is to minimize

the weight gain often associated with intensive insulin therapy and is

best achieved by placing limits on carbohydrate intake.

The goals of MNT in type 2 DM should focus on weight loss and

address the greatly increased prevalence of cardiovascular risk factors

(hypertension, dyslipidemia, obesity) and disease in this population.

The majority of these individuals are obese, and weight loss is strongly

encouraged. Very-low-carbohydrate diets that induce weight loss may

result in rapid and dramatic glucose lowering in individuals with

new-onset type 2 DM. MNT for type 2 DM should emphasize modest

caloric reduction, increased physical activity, and weight loss (goal

of at least 5–10% loss). Weight loss and exercise each independently

improve insulin sensitivity.

Fasting for religious reasons, such as during Ramadan, presents a

challenge for individuals with diabetes, especially those taking medications to lower the plasma glucose. Under International Diabetes Federation (IDF) guidelines on fasting during Ramadan, individuals are

risk-stratified as those who can safely fast with medical evaluation and

supervision and those in whom fasting is not advised. Thus, patient

education and regular glucose monitoring are critical.

Physical Activity Exercise has multiple positive benefits including

cardiovascular risk reduction, reduced blood pressure, maintenance of

muscle mass, reduction in body fat, and weight loss. For individuals with

type 1 or type 2 DM, exercise is also useful for lowering plasma glucose

(during and following exercise) and increasing insulin sensitivity. In

patients with diabetes, the ADA recommends 150 min/week (distributed

over at least 3 days) of moderate aerobic physical activity with no gaps

longer than 2 days. Resistance exercise, flexibility and balance training,

and reduced sedentary behavior throughout the day are advised.

Despite its benefits, exercise may present challenges for some

individuals with DM because they lack the normal glucoregulatory

mechanisms (normally, insulin falls and glucagon rises during exercise). Skeletal muscle is a major site for metabolic fuel consumption

in the resting state, and the increased muscle activity during vigorous,

aerobic exercise greatly increases fuel requirements. Individuals with

type 1 DM are prone to either hyperglycemia or hypoglycemia during

exercise, depending on the preexercise plasma glucose, the circulating

insulin level, lactate, and the level of exercise-induced catecholamines.

If the insulin level is too low, the delivery of lactate to the liver and

rise in catecholamines may increase the plasma glucose excessively,

promote ketone body formation, and possibly lead to ketoacidosis.

Conversely, if the circulating insulin level is excessive, this relative

hyperinsulinemia may reduce hepatic glucose production (decreased

glycogenolysis, decreased gluconeogenesis) and increase glucose entry

into muscle, leading to hypoglycemia.

To avoid exercise-related hyper- or hypoglycemia, individuals with

type 1 DM should (1) monitor blood glucose before, during, and after

exercise; (2) delay exercise if blood glucose is >14 mmol/L (250 mg/

dL) and ketones are present; (3) if the blood glucose is <5.0 mmol/L

(90 mg/dL), ingest carbohydrate before exercising; (4) monitor glucose

during exercise and ingest carbohydrate as needed to prevent hypoglycemia; (5) decrease insulin doses (based on previous experience)

before and after exercise and inject insulin into a nonexercising area;

and (6) learn individual glucose responses to different types of exercise. In individuals with type 2 DM, exercise-related hypoglycemia

is less common but can occur in individuals taking either insulin or

insulin secretagogues. Untreated proliferative retinopathy is a relative

contraindication to vigorous exercise, because this may lead to vitreous

hemorrhage or retinal detachment (Chap. 405).

Psychosocial Care Because the individual with DM faces challenges that affect many aspects of daily life, psychosocial assessment

and support are a critical part of comprehensive diabetes care. The

patient should view himself/herself as an essential member of the diabetes care team and not as someone who is cared for by the diabetes

management team. Even with considerable effort, normoglycemia can

be an elusive goal, and solutions to worsening glycemic control may

not be easily identifiable. Depression, anxiety, or “diabetes distress,”

defined by the ADA as “…negative psychological reactions related to

TABLE 404-3 Nutritional Recommendations for Adults with Diabetes

or Prediabetesa

General dietary guidelines

• Vegetable, fruits, whole grains, legumes, low-fat dairy products and food

higher in fiber and lower in glycemic content; optimal diet composition and

eating pattens are not known

Fat in diet (optimal % of diet is not known; should be individualized)

• Mediterranean-style diet rich in monounsaturated and polyunsaturated fatty

acids

• Minimal or no trans fat consumption

Carbohydrate in diet (optimal % of diet is not known; should be individualized)

• Monitor carbohydrate intake in regard to calories and set limits for meals to

reduce postprandial glycemia

• Avoid fructose- and sucrose-containing beverages and minimize consumption

of foods with added sugar that may displace healthier, more nutrient-dense

food choices and elevate postprandial glycemia

• Estimate grams of carbohydrate in diet for flexible insulin dosing (type 1 DM

and insulin-dependent type 2 DM)

• Consider using glycemic index to predict how consumption of a particular

food may affect blood glucose

Protein in diet (optimal % of diet is not known; should be individualized)

Other components

• Reduced-calorie and nonnutritive sweeteners may be useful

• Routine supplements of vitamins, antioxidants, or trace elements not

supported by evidence

• Sodium intake as advised for general population

a

See text for differences for patients with type 1 or type 2 diabetes.

Source: Data from American Diabetes Association: 5. Facilitating behavior

change and well-being to improve health outcomes: Standards of medical care in

diabetes-2021. Diabetes Care 44(Suppl 1):S53, 2021.

prevention and management of hypoglycemia (Chap. 406); foot and

skin care; diabetes management before, during, and after exercise; and

risk factor–modifying activities. The focus is providing patient-centered, individualized education. More frequent contact between the

patient and the diabetes management team (e.g., electronic, telephone,

video) improves glycemic control.

Nutrition Therapy Medical nutrition therapy (MNT) is a term

used by the ADA to describe the optimal coordination of caloric intake

with other aspects of diabetes therapy (insulin, exercise, and weight

loss). Some aspects of MNT are directed at preventing or delaying the

onset of type 2 DM in high-risk individuals (obese or with prediabetes)

by promoting weight reduction. Other measures of MNT are directed

at improving glycemic control through limiting carbohydrate intake

and avoiding simple sugars and fructose and managing diabetesrelated complications (cardiovascular disease [CVD], nephropathy).

Medical treatment of obesity including pharmacologic approaches that

facilitate weight loss and metabolic surgery should be considered in

selected patients (Chaps. 401 and 402).

In general, the components of optimal MNT are similar for individuals with type 1 or type 2 DM—high-quality, nutrient-dense with

limits on carbohydrate intake required for glycemic control and weight

management (Table 404-3). The data are currently inconclusive about

various eating patterns (intermittent fasting, etc.). Dietary advice

should be individualized, acknowledging personal preferences, culture,

and religious traditions. Using the glycemic index, an estimate of the

postprandial rise in the blood glucose when a certain amount of that

food is consumed, may reduce postprandial glucose excursions and

improve glycemic control.

The goal of MNT in type 1 DM is to coordinate and match the carbohydrate intake, both temporally and quantitatively, with the appropriate amount of insulin. MNT in type 1 DM is informed by SMBG

and/or CGM that should be integrated to define the optimal insulin

regimen. Based on the patient’s estimate of the carbohydrate content of

a meal, an insulin-to-carbohydrate ratio determines the bolus insulin

dose for a meal or snack. MNT must be flexible enough to allow for

exercise, and the insulin regimen must allow for variations in caloric