Evaluation of hyperglycemia

Hyperglycemia: acute versus chronic

Hyperglycemia is defined as an elevated plasma glucose (PG) concentration. Hyperglycemia can be classified as transient (acute) or sustained (chronic). Chronic hyperglycemia constitutes diabetes mellitus (which will be referred to as “diabetes” in the rest of the chapter; other than Wolfram syndrome, diabetes insipidus will not be discussed). Specific PG cutpoints defining diabetes mellitus are discussed below.

Causes of transient hyperglycemia are listed in Table 8.1 . Diabetes is a family of metabolic diseases characterized by sustained (chronic) hyperglycemia . In some cases, prolonged use of a medication such as glucocorticoids or an atypical antipsychotic medication causes diabetes. However, discontinuation of these medications may lead to a reversal of the diabetic state.

Table 8.1

Causes of transient hyperglycemia.

Significant degrees of metabolic stress (secondary to elevations in the antiinsulin stress hormones: glucagon, epinephrine, cortisol, and growth hormone)
Myocardial infarction
Acute, severe illness
Medications used for short durations of time (e.g., only days to weeks)
Glucocorticoids (antiinsulin stress hormones)
Catecholamines (antiinsulin stress hormones)
Growth hormone (an antiinsulin stress hormone)
Oral contraceptives (causes insulin resistance)
Thiazides (causes insulin resistance)
Furosemide (causes potassium depletion)
Iatrogenic etiologies (excessive rates of parenteral glucose infusion)
Intravenous glucose infusion
Acute pancreatitis (transient pancreatic islet-cell dysfunction)
Head injury (dysfunctional autonomic control of the pancreatic islets)

Pathophysiologically, diabetes results from a decline in insulin action. Insulin action is the approximate multiplicative product of the absolute insulin concentration and the insulin sensitivity of the tissues. The three major targets for insulin action are the liver, muscle, and adipose tissue. In the liver, insulin stimulates glycolysis, sparing free fatty acids for triglyceride synthesis. Gluconeogenesis is suppressed, making amino acids available for protein synthesis. Insulin promotes energy storage through stimulation of glycogen synthesis. The net effect of insulin on the liver is increased glucose utilization and decreased hepatic glucose output. Recall that during the fasting state, the source of circulating glucose is the liver. During fasting, glucose is initially provided through glycogenolysis, whereas some 12–18 h later, significant gluconeogenesis is occurring.

In muscle and adipose tissue, insulin stimulates the migration of insulin-responsive glucose transporters (GLUT4; SLC2A4; solute carrier family 2 member 4; chromosome 17p13.1) to the cell membrane, permitting increased rates of glucose uptake by these tissues. GLUT4 is a nonenergy-requiring facilitative GLUT. Adipose tissue burns glucose to acetate (e.g., acetyl coenzyme A) that is substrate for fatty acid synthesis and subsequent triglyceride synthesis. While burning glucose for energy, muscle will also store glucose as muscle glycogen to a limited degree. All three tissues increase glucose clearance from the circulation with a resultant fall in PG concentrations following meals.

Clinical symptoms of diabetes

When the PG concentration exceeds the renal threshold for glucose (e.g., more glucose is filtered by the glomerulus than can be reabsorbed by the renal tubules), glycosuria results. Because of the resulting elevated urine osmolality, a diuresis ensues that is clinically evident as polyuria (increased urination). Electrolytes lost during this osmotic diuresis include sodium, potassium, magnesium, and phosphate.

Hyperglycemic patients will frequently begin to void at night (nocturia), whereas children may experience bed-wetting (enuresis). With increased urinary fluid loss, thirst is stimulated, causing increased drinking (polydipsia). Because of diminished insulin action, adipose tissue lipolysis increases. As well, protein catabolism accelerates to provide amino acid carbon skeletons for gluconeogenesis by the liver. The clinical consequence of this catabolic state is weight loss in patients with severe insulin deficiency. Fat breakdown fueling ketogenesis also contributes to weight loss. Some patients experience increased appetite (e.g., polyphagia) because large amounts of calories are lost in the urine. Blurred vision may occur resulting from fluid shifts involving the lens of the eye secondary to hyperglycemia. Children who are in very poor diabetic control may grow poorly (e.g., Mauriac syndrome). However, poor growth in diabetic children is the exception and not the rule. Usually, diabetic children grow well even if they are in poor glycemic control.

Chronic hyperglycemia affects the skin and connective tissues. The skin over the backs of the hands becomes palpably thickened with reduced flexibility . Joints become stiff with reduced range of motion. If the patient is asked to oppose the fingers and palms of the hands, because of limited joint mobility, the fingers do not approximate one another at the proximal or distal interphalangeal joints (e.g., the “prayer” sign). The wrists, elbows, and neck can be affected. These changes are believed to reflect a nonenzymatic glycation of connective tissue proteins.

Hyperglycemia clearly impairs phagocyte function . When impaired innate (e.g., intrinsic or natural immunity) immunity is combined with the nutrient-rich tissue and body fluid conditions provided by hyperglycemia, increased susceptibility to bacterial and fungal infections often occurs in patients with poorly controlled diabetes. Diabetic subjects are predisposed to soft tissue infections, balanitis (infection of the space between the foreskin and glans), vaginitis, and urinary tract infections.

Severe acute insulin deficiency in patients with type 1 diabetes can precipitate diabetic ketoacidosis (DKA). Less commonly, DKA develops in severely stressed patients with type 2 diabetes. In DKA, the rate of ketone body production exceeds the rate of ketone body consumption. The accumulation of acetoacetic acid and β-hydroxybutyric acid leads to an anion-gap, normochloremic acidosis. Hyperglycemia leads to acute dehydration through an excessive osmotic diuresis. Because ketosis can cause nausea and vomiting, patients are less likely to drink further, which increases the degree of dehydration. With poor tissue perfusion, lactic acidosis may additionally develop. Untreated, profound acidosis can lead to cardiovascular failure and death. Children are at risk of developing cerebral edema, which can cause death. DKA is fatal in 10%–15% of adults and 0.5% of children who experience this condition. When severe hyperglycemia occurs in patients with type 2 diabetes who then suffer profound dehydration, the hyperglycemic hyperosmolar state [HHS; previously termed: hyperglycemic nonketotic coma (HNKC)] can ensue, with a consequent high mortality rate. Patients with HHS have minimal or no ketosis and minimal or no acidosis.

For patients who have had diabetes for 10 or more years, there is an increasing likelihood that they will experience diabetic complications. These problems include macrovascular, microvascular, and neuropathic diseases. Macrovascular disease may present as angina, heart attack (myocardial infarction), heart failure (chronic coronary artery disease), stroke (cerebrovascular disease), or claudication (peripheral vascular disease). Claudication is the fatigue and pain that patients experience in their legs when walking when there is inadequate blood supply to match oxygen demand.

Microvascular disease produces retinopathy and nephropathy. Retinopathy can lead to blindness, whereas nephropathy can lead to renal failure. Retinopathy is classified as background (nonproliferative) or proliferative (e.g., there is new blood vessel formation over the surface of the retina). Peripheral neuropathy can produce loss of sensation in the feet and hands. Painful peripheral neuropathy can be incapacitating. Autonomic neuropathy may be evidenced in gastroparesis (decreased gastrointestinal tract motility), impotence, decreased sexual response in women, postural hypotension (low blood pressure upon arising from the sitting or supine position often accompanied by light-headedness or fainting), and loss of the normal beat-to-beat variation in heart rate that occurs with breathing. Autonomic neuropathy may play a role in the development of hypoglycemia in persons with diabetes.

Classification of diabetes

Chronic (sustained) hyperglycemia may be permanent (e.g., type 1 or type 2 diabetes) or time-limited [e.g., gestational diabetes mellitus (GDM) (diabetes first recognized during the second or third trimester of pregnancy that resolves following delivery)]. Diabetes is classified into four major types ( Table 8.2 ). The classification of diabetes is based upon etiology and not the type of therapy that a patient receives. The nomenclature “insulin-dependent diabetes,” “type I (Roman numeral) diabetes,” “noninsulin-dependent diabetes,” and “type II (Roman numeral) diabetes” is replaced, respectively, by the terms type 1 (Arabic) and type 2 (Arabic) diabetes.

Table 8.2

Classification of diabetes.

Type 1 diabetes
Type 2 diabetes
Other specific types of diabetes
Gestational diabetes mellitus (GDM)

Type 1 diabetes

Type 1 diabetes results from absolute insulinopenia (low insulin concentration in the bloodstream). Insulinopenia most commonly results from autoimmune destruction of the insulin-producing β cells. This condition is frequently accompanied by the expression of several islet autoantibodies that can be recognized at or before the time of diagnosis of type 1 diabetes: islet cell cytoplasmic autoantibodies (ICAs), insulin autoantibodies (IAAs), glutamic acid decarboxylase autoantibodies (GADAs), insulinoma-associated-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8A) . ICAs are detected by indirect immunofluorescence, whereas IAAs, GADAs, IA-2As, and ZnT8A are detected by a variety of immunoassays [immunoprecipitation, ELISA with a spacer for the autoantigen, luciferase immunoprecipitation system, electrochemiluminescence, etc.]. The presence of any of these autoantibodies indicates an autoimmune etiology for diabetes and classification as type 1A diabetes. IAA must be measured prior to insulin administration because after ~14 days exogenous insulin injection can induce insulin antibodies that cannot be distinguished analytically from IAA.

If the clinical differentiation between type 1 and type 2 diabetes is problematic in a patient, measurement of islet autoantibodies should strongly be considered. Such instances include obese patients presenting with DKA or lean patients previously diagnosed with type 2 diabetes that progress to insulin dependence. When the cause of the insulinopenia is unidentified in type 1 diabetes, diabetes is classified as type 1B diabetes. Type 1B diabetes is rare and may be caused by viral infection . Viruses proposed to trigger type 1 diabetes include coxsackie A and B viruses, cytomegalovirus, ECHO virus , Epstein–Barr virus, rubella virus , mumps virus, and retroviruses.

Because type 1A diabetes is far more common than type 1B diabetes, type 1A diabetes will hereafter be referred to simply as “type 1 diabetes.” If a specific nonautoimmune etiology for the insulinopenia is identified [e.g., β cell destruction from Vacor (rat poison)], the diabetes is then classified under the heading of “other specific types of diabetes” (see below).

Type 2 diabetes

Type 2 diabetes results from a combination of tissue insulin resistance and relative β cell failure (e.g., relative insulinopenia) . Relative insulinopenia infers that even if the absolute concentration of insulin in the circulation is greater than normal, the supranormal insulin concentration is still insufficient to correct the patient’s hyperglycemia. Insulin resistance is most often postreceptor; for example, the insulin receptor is structurally normal; however, there is deficient generation of second messengers within the target cell, leading to decreased insulin action. Accompanying most forms of diabetes is hyperglucagonemia.

Type 2 diabetes is commonly part of the metabolic syndrome (see below). There is no consensus definition of the metabolic syndrome among professionals . Because of the impact of the metabolic syndrome on health, life expectancy in the United States may decline in the 21st century . Features of the metabolic syndrome are listed in Table 8.3 .

Table 8.3

Features of the metabolic syndrome.

Centripetal obesity
Insulin resistance
Elevated apolipoprotein B
Dense LDL particles
Type 2 diabetes
Nonalcoholic fatty liver
Nonalcoholic steatohepatitis
Elevated ferritin
Elevated C-reactive protein (CRP)
Elevated fibrinogen
Polycystic ovarian syndrome
Male menopause (andropause) (under investigation)
Acanthosis nigricans

Metabolic syndrome

The metabolic syndrome is a group of reproducible, recognizable characteristics that relate insulin resistance and central obesity to increased cardiovascular risk, as well as several other health problems . Central obesity is defined as an increased abdominal circumference where there is an increased waste-to-hip ratio. The distribution of fat in central obesity is both subcutaneous and intra-abdominal; however, it is the intra-abdominal (e.g., visceral or omental fat) that is most strongly correlated with insulin resistance and adverse outcomes .

Several terms have been applied to the metabolic syndrome including the insulin resistance syndrome, syndrome X, the diabesity syndrome, the morbesity syndrome, the cardiometabolic syndrome, and the dysmetabolic syndrome X (ICD-10 code: E88.81). The metabolic syndrome has been defined by the NIH as “… a group of risk factors linked to overweight and obesity that increase the patient’s chance for heart disease and other health problems such as diabetes and stroke” .

There are at least four major hypotheses linking obesity and insulin resistance. (1) Free fatty acid levels in the blood are elevated in the metabolic syndrome . Elevated free fatty acid levels in obesity can lead to triglyceride deposition in the liver, skeletal muscle, and beta cells . Such fat deposition in the liver and skeletal muscle interferes with insulin signaling reducing insulin’s effect on these tissues. From the uptake of free fatty acids by tissues, the resulting diacyl glycerol may affect second messenger signaling of the insulin receptor. Fat deposition damages the beta cells contributing to relative insulinopenia in type 2 diabetes. (2) As muscle is “marbled” (a.k.a.—infiltrated) with increased numbers of fat cells that accompany obesity, these adipocytes locally produce tumor necrosis factor-alpha (TNF-α) inducing skeletal muscle insulin resistance . It is worth noting that skeletal is quantitatively the major site of glucose clearance. (3) Adipose tissue is not a passive receptor or distributor of fat and fatty acids. Adipose tissue regulates systemic insulin sensitivity through the production of many adipokines including adiponectin. Deficient adiponectin in the metabolic syndrome leads to decrease insulin sensitivity and produces a pro-inflammatory and a pro-atherogenic state . (4) With the conversion of circulating steroids to cortisol in adipose via the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an element of hypercortisolism may be present in the metabolic syndrome . Despite the above evidence, there is a growing body of evidence that proposes that beta-cell hyperresponsiveness may drive the metabolic syndrome .

Pathophysiologically, the consequences of the metabolic syndrome can be divided into (1) those consequences that result from hyperinsulinism that is an attempted compensation for insulin resistance, and (2) those consequences that result from inadequate insulinization despite elevated circulating insulin levels, or, later in the course of the metabolic syndrome, declining beta-cell insulin secretion .

Metabolic syndrome consequences that result from hyperinsulinism

Hyperinsulinism has been associated with atherosclerosis . Certainly insulin serves as a growth factor. It is controversial if atherogenesis is caused by hyperinsulinism, or whether atherogenesis is merely associated with hyperinsulinism.

There is a strong association between hyperinsulinism and hypertension . Hyperinsulinism causes sodium and water retention that could increase circulating blood volume (at least transiently). Hyperinsulinism increases sympathetic tone causing vasoconstriction. Next, hyperinsulinism appears to induce vascular hypertrophy causing vasoconstriction. Lastly, hyperinsulinism increases the activity of the Na + /K + ATPase pump causing vasoconstriction. These factors contribute to the development of hypertension in persons affected with the metabolic syndrome.

Hyperinsulinism causes hypercoagulability which is pro-atherogenic. Insulin stimulates the production of plasminogen activator inhibitor-1 (PAI-1) . Normally tissue plasminogen activator (tPA) stimulates the conversion of plasminogen to plasmin with plasmin-causing fibrinolysis. However, PAI-1 inhibits tPA creating a pro-thrombotic state. Because the metabolic syndrome is a pro-inflammatory state, additionally levels of factor VIII and fibrinogen are elevated.

Hyperinsulinism contributes to hyperuricemia and gout through increased uric acid reabsorption . Urinary sodium and urate reabsorption are linked: both are increased by insulin. Increased plasma uric acid predisposes to gout, which occurs commonly in persons with the metabolic syndrome. There is intriguing data that uric acid may be pro-atherogenic .

Hyperandrogenism in women is linked to hyperinsulinism . A serious clinical manifestation of hyperandrogenism is the polycystic ovarian syndrome . Pituitary FSH is suppressed and LH is stimulated by elevated insulin levels. Together with elevated LH, high insulin levels stimulate ovarian overproduction of androgens. Hyperinsulinism lowers hepatic sex hormone binding globulin (SHBG) production. Reduced SHBG and elevated total testosterone levels raise free testosterone levels causing hirsutism, menstrual irregularities, and even infertility in women . By causing salt retention, which raises blood pressure, increasing low-density lipoproteins (LDL)-cholesterol, and lowering high-density lipoproteins-cholesterol (HDL-C), hyperandrogenism fosters a pro-atherogenic state.

Acanthosis nigricans is a cutaneous manifestation of hyperinsulinism . Acanthosis nigricans is characterized by velvety, warty benign growths and hyperpigmentation localized in areas of skin friction: the axillae, neck, anogenital area, and groin . The differential diagnosis of acanthosis nigricans additionally includes malignancy, endocrine disorders, and obesity.

Metabolic syndrome consequences that result from inadequate insulinization

Within insufficient insulin action despite elevations in the absolute circulating insulin concentration, three major consequences can result: (1) dysglycemia (abnormal glucose metabolism manifested as prediabetes or frank diabetes), (2) dyslipidemia, and (3) nonalcoholic fatty liver (NAFL) disease.

The pathophysiology of dysglycemia is the pathophysiology of type 2 diabetes as discussed elsewhere in this chapter . Normal glucose tolerance can progress to postmeal-challenge glucose intolerance, to fasting hyperglycemia, to frank type 2 diabetes. Type 2 diabetes is a rather late manifestation of the metabolic syndrome.

High glucose and low levels of insulin action foster a pro-inflammatory state. Consequently, the metabolic syndrome is recognized as a state of heightened inflammation with elevated levels of ferritin, C-reactive protein, serum amyloid A, and fibrinogen . Increased glucose concentrations increase the transcription factors NFkappaB, activator protein-1 (AP-1), I kappa B kinase-alpha and IKK B, p47phox (a cytoplasmic NADPH oxidase subunit), the cytokines IL-1, IL-6, and TNF-α, expression of ICAM-1 and E-selectins, matrix metalloproteinases, and reactive oxygen species. Increased glucose decreases cytoplasmic I kappa B which regulates NFkappaB. On the other hand, increased insulin action decreases the transcription factors NFkappaB (and may decrease VGEF, TNF-α, and IL-6), AP-1 (that regulates metalloproteinases), and early growth response-1 (Egr-1; that regulates PAI-1 and tissue factor expression), ICAM-1, MCP-1, CRP, reactive oxygen species, and p47phox. Increased insulin action increases cytoplasmic I kappaB.

In terms of lipids, insulin resistance is manifested as hypertriglyceridemia, low HDL-C, increased apo-B concentrations, and dense LDL particles . Please see Chapter 9 for a formal discussion of such dyslipidemias.

With increased levels of free fatty acids coursing through the liver, fatty infiltration of the liver is an increasingly common finding in the metabolic syndrome . Such “nonalcoholic fatty liver” (NAFL) can progress through inflammation to “nonalcoholic steatohepatitis” (NASH). NASH can progress to cirrhosis or liver failure and predisposes to hepatocellular carcinoma. Elevated alanine aminotransferase (ALT) levels are not particularly sensitive markers of NAFL and related disorders. Abnormal ultrasound findings do correlate more closely with fatty infiltration .

The reader is referred to several recent reviews on the topic of the metabolic syndrome .

Other specific types of diabetes

Other specific types of diabetes are classified into eight subtypes ( Table 8.4 ).

Table 8.4

Subtypes of “other specific types of diabetes.”

Genetic defects of β cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Drug- or chemical-induced diabetes
Uncommon forms of immune-mediated diabetes
Other genetic syndromes associated with diabetes

Genetic defects of β cell function

Genetic defects of β cell function include inborn errors causing insulinopenic diabetes. Examples include: (1) maturity-onset diabetes of youth (MODY) ( Tables 8.5 and 8.6 ), (2) neonatal diabetes due to several inborn errors, (3) mitochondrial diabetes, (4) familial hyperproinsulinemia, and (5) insulinopathies. For individuals 35 years of age and younger, the likelihood of MODY can be calculated on-line .

Table 8.5

Causes of maturity-onset diabetes of youth.

Disorder Mutated protein Abbreviation
MODY1 Hepatocyte nuclear factor 4α HNF-4α
MODY2 Glucokinase GCK
MODY3 Hepatocyte nuclear factor 1α (a.k.a.—transcription factor 1, TCF-1) HNF-1α
MODY4 Pancreatic and duodenal homeobox protein 1 (a.k.a.—insulin promoter factor 1, IPF-1) PDX1
MODY5 Hepatocyte nuclear factor 1β HNF-1β
MODY6 Neuro D/beta 2
MODY7 Krüppel-like factor 11 KLF11
MODY8 Carboxyl ester lipase CEL
MODY9 Paired box gene 4 PAX4
MODY10 Insulin INS
MODY11 B-lymphocyte kinase BLK
MODY12 Sulfonylurea receptor 1 SUR1
MODY13 A beta-cell potassium channel Kir6.2

Table 8.6

Notable clinical features of the maturity-onset diabetes of youth syndromes.

Disorder Comment
MODY1 Progressive insulinopenia; management with sulfonylureas for decades; complications can occur; possible: decreased apolipoprotein (apo) C2, apo C3, lipoprotein(a), and triglycerides; increased birth weight; possible neonatal hyperinsulinism; ~80% penetrance by age 40 .
MODY2 Nonprogressive insulinopenia; management without drugs is common; complications are uncommon; decreased birth weight; ~50% penetrance by age 40; common cause of MODY .
MODY3 Progressive insulinopenia; complications can occur; decreased birth weight; ~80% penetrance by age 40; common cause of MODY .
MODY4 Homozygosity causes pancreatic agenesis; affected individuals can present with GDM-like or a type 2 diabetes-like phenotype .
MODY5 Possible: renal cysts, vaginal/uterine malformations, abnormal liver function, nondiabetic renal disease .
MODY6 Low penetrance; can cause neurological abnormalities (e.g., intellectual disability) .
MODY7 Rare cause of MODY .
MODY8 Exocrine pancreatic dysfunction .
MODY9 Severe diabetic complications .
MODY10 Described in a Chinese man presenting with “type 2 diabetes” at age 31 years; INS mutations can cause neonatal diabetes .
MODY11 BLK modulates insulin synthesis and secretion .
MODY 12 Also a common cause of neonatal diabetes; gene name: ATP-binding cassette, subfamily C, member 8 (ABCC8) .
MODY 13 Also a common cause of neonatal diabetes; gene name: potassium channel, inwardly rectifying, subfamily J, member 11 (KCNJ11) .

Maturity-onset diabetes of youth

MODY is defined as nonketotic, initially noninsulin-requiring diabetes with onset before age 25 that is inherited in an autosomal dominant (single gene) pattern ( Table 8.5 ). Presently 13 types of MODY have been described . Most forms of MODY appear to result from β cell defects. Several forms of MODY can present in infancy or, more commonly, childhood, adolescence, or early adulthood ( Table 8.6 ).

Islet-1 (chromosome 5q11-q13) is a Lim domain homeobox gene that encodes a transcription factor that regulates insulin expression . While being associated with type 2 diabetes in a few families, islet-1 has not been associated (so far) with MODY .

Gene sequencing has become the most effective means to diagnose MODY (and neonatal diabetes, see below) . As with any diagnosis based on a gene sequence, the significance of novel mutations requires careful consideration . The case for routine DNA sequencing in infants and children with type 1 diabetes or neonatal diabetes has been made .

Neonatal diabetes

Strictly speaking, neonatal diabetes mellitus (NDM) is diabetes diagnosed within the first 28 days of life. However, the window of time for the diagnosis of diabetes is extended by some experts to 6 or even 12 months of age. NDM is a rare condition with prevalence estimates of 1 in 200,000 to 1 in 800,000 newborns, with the median estimate of 1 in 400,000. NDM can be permanent (PNDM) or transient (TNDM). Furthermore, later in childhood permanent diabetes can occur in individuals with initially TNDM. Genetic mutations causing neonatal diabetes are listed in Table 8.7 .

Table 8.7

Monogenic causes of neonatal diabetes.

Permanent diabetes (PNDM) Transient diabetes (TNDM)
Imprinting anomalies on chromosome 6q24 a X
KATP channel
Kir6.2 mutations X X
SUR1 mutations X X
Transcription factor
HNF-1α (MODY3) X
HNF-1β (MODY5) X X
IPEX syndrome X
NKX2-2 X
Transmembrane endoplasmic reticulum protein
WFS1 X b

a Hypoglycemia is possible in infancy or childhood.

b Due to the rare autosomal dominant form of Wolfran syndrome, autosomal recessive Wolfran syndrome presents in childhood.

Imprinting abnormalities of genes on chromosome 6 (6q24) are the most commonly recognized cause of TNDM . Besides neonatal diabetes, usually diagnosed in the first week of life, characteristic features of these disorders include severe intrauterine growth retardation, resolution of hyperglycemia by age 18 months (but usually by 12 weeks of age), fluid depletion, and lack of ketoacidosis. Intrauterine growth retardation results from insulin deficiency in utero. In utero, insulin is extremely important for growth. Other findings can include umbilical hernia and macroglossia. Diabetes recurs in approximately 50% of cases during childhood. Initially, the diabetes may be responsive to oral hypoglycemic agents, although insulin is often required with recurrence of the diabetes later in life.

Within the 6q24 differentially methylated region of chromosome 6q24, relative hypomethylation leads to increased expression of the PLAGL1 (PLAG1 like zinc finger 1; chromosome 6q24.2) and HYMAI (hydatidiform mole-associated and imprinted transcript; chromosome 6q24.2) which are imprinted genes. Other genetic mechanisms have also been described (e.g., paternal gene duplication of 6q24 and chromosome 6 paternal uniparental disomy). PLAGL1 (a.k.a.— ZAC; zinc-finger protein that regulates apoptosis and cell cycle arrest) is the “pleomorphic adenoma of the salivary gland gene like 1” and is a tumor suppressor gene. This DNA-binding protein is widely expressed and regulates apoptosis. Mutations in ZFP57 , a transcription factor (ZFP57 zinc finger protein; chromosome 6p22.1) needed for normal methylation maintenance during embryonic development, commonly also occur .

Gain-of-function mutations in the β cell inwardly rectified potassium channel (K ATP ) can cause permanent or transient neonatal diabetes . Such mutations (where K ATP does not close) inhibit β cell depolarization, causing insulinopenia. Four Kir6.2 subunits constitute the actual potassium channel, whereas four sulfonylurea receptor-1 (SUR1) subunits regulate Kir6.2. These are the most common causes of PNDM. Kir6.2 is encoded by the gene KCNJ11 (potassium inwardly rectifying channel subfamily J member 11; chromosome 11p15.1), and SUR1 is encoded by ABCC8 (ATP-binding cassette subfamily C-branch member 8; chromosome 11p15.1). Developmental delay and epilepsy have been recognized in individuals with severe KCNJ11 mutations. Such findings together with NDM are termed the DEND (developmental delay, epilepsy, neonatal diabetes) syndrome. SUR1 is expressed in pancreatic β cells and neurons, whereas SUR2A is expressed in the heart, and SUR2B is expressed in smooth muscle. Molecular analysis of KCNJ11 and ABCC8 is available commercially in the United States. Both disorders respond to sulfonylureas. This strengthens the case for molecular testing to establish such diagnoses where insulin injections are not the treatment of choice.

Various transcription factor mutations can lead to insulinopenia and possibly a disturbance in pancreatic or islet neogenesis in utero. HNF stands for hepatocyte nuclear factor. PDX1 (chromosome 13q12.2) stands for “Pancreatic and Duodenal Homeobox 1,” whereas IPF stands for “insulin promotor factor.” HNF-1α (MODY3; HNF1 homeobox A; chromosome 12q24.31) or HNF-1β (MODY5; HNF1 homeobox B; chromosome 17q12) mutations can cause NDM. Except for HNF1β mutations that can cause transient or permanent diabetes, the other transcription factor mutations cause permanent diabetes . Homozygosity or compound heterozygosity for mutations in PDX1 (IPF1; MODY4) is one cause of pancreatic agenesis .

The rare immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome can cause neonatal diabetes . The mutation in this syndrome involves the forked-head transcription factor FOXP3 (forkhead box P3; chromosome Xp11.23). FOXP3 expression is a feature of CD4+CD25+ regulatory T cells. This is not a disorder of intrinsic β cell development or insulin gene regulation. IPEX is an autoimmune disease.

PTF1A is “pancreas transcription factor 1A” (chromosome 10p12.2). In the rare condition of homozygous PTF1A mutations, PNDM results that can be accompanied by pancreatic and cerebellar agenesis . Another autosomal recessive transcription factor disorder results from mutations in RFX6 (regulatory factor X6; chromosome 6q22.1). RFX6 is necessary for normal β- cell development . Homozygous RFX6 mutations have been reported in Mitchell–Riley syndrome, which is characterized by NDM, severe intrauterine growth retardation, agenesis of the gallbladder, cholestasis, intestinal malrotation, annular pancreas, and chronic diarrhea .

GATA4 (GATA binding protein 4; chromosome 8p23.1) encodes a zinc-finger transcription factor that regulates several genes involved in embryogenesis (including pancreatic development). Neonatal and childhood-onset diabetes can result from mutations in GATA4 . Congenital heart defects are frequent in persons with mutations of GATA4 . Haploinsufficiency of GATA6 (GATA binding protein 6; chromosome 18q11.2) has caused pancreatic agenesis with neonatal diabetes .

GLIS3 (GLIS family zinc finger 3; chromosome 9p24.2) codes for a zinc-finger protein transcription factor. Mutations can cause neonatal diabetes and congenital hypothyroidism . Discovery of the cause of neonatal diabetes is more than academic; specific therapies are under development in addition to the targeted use of sulfonylureas in MODY1 and MODY3 .

NEUROG3 (neurogenin 3; chromosome 10q22.1) codes for a basic helix-loop-helix transcription factor that plays a role in neurogenesis. Defects in the expressed protein result in malabsorptive diarrhea from early in life. Neonatal diabetes may or may not be present . NEUROG3 is being investigated in reprogramming cells into β cells .

NEUROD1 (neuronal differentiation 1; chromosome 2q31.3) mutations are recognized causes of MODY (i.e., MODY6). A report indicates that at least one NEUROD1 mutation can cause neonatal diabetes with neurological problems . This emphasizes the concept that neonatal diabetes and MODY form a continuum of types of monogenic diabetes .

A patient with Down syndrome and neonatal diabetes, hypopituitarism, microphthalmia, and a brain malformation has been reported with compound heterozygous PAX6 mutations . PAX6 (paired box 6; chromosome 11p13) is involved in eye development, as well as, the development of other tissues.

NKX2-2 (NK2 homeobox 2; chromosome 20p11.22) is a homeobox domain transcription factor. NKX2-2 mutations cause neonatal diabetes. Three affected children were small for gestation age (consistent with in utero insulin deficiency), displayed normal exocrine pancreatic function, exhibited developmental delay and short stature . This same paper reports reduced birth weight and neonatal diabetes with normal exocrine pancreatic function associated with MNX1 mutations. MNX1 (motor neuron and pancreas homeobox 1; chromosome 7q36.3) encodes a homeobox domain transcription factor.

The linkage between the site of transcription factor action and its effect on diabetogenesis and pancreatic exocrine and endocrine organogenesis is displayed in Table 8.8 . In the table, the arrows (i.e., “→” and “↔”) indicate which cell gives rise to the next cell in development. Note that the tip and trunk progenitors can interconvert. In the table, transcription factors are in bold . In this model the pancreatic endoderm gives rise to the pancreatic progenitors. Tip-trunk progenitors are derived from the pancreatic progenitors. The tip progenitors give rise to acinar cells, whereas the trunk progenitors give rise to duct cells and islet cell precursors that develop into α or β cells.

Table 8.8

Genes causing monogenic forms of diabetes (MODY and/or neonatal diabetes) and their role in pancreatic organogenesis.

Cell type Transcription factors expressed that can cause monogenic diabetes
Pancreatic endoderm PDX1 , PTF1A , GATA4 , MNX1 , RFX6
Pancreatic progenitors PDX1 , PTF1A , GATA4 , GATA6 , HNF1B , GLIS3 , MNX1
Tip-trunk progenitors
Tip PDX1 , PTF1A , GATA4 → Acinar cell PTF1A , GATA4
Trunk PDX1 , HNF1B → Duct cell PDX1 , HNF1B
→Islet precursor NKX2.2 → β cell PDX1 , NKX2.2 , RFX6 , PAX6 ,
→ α cell NKX2.2 , PAX6

As suggested from studies in mice, there is also a hierarchy of associated transcription factors that regulate, in part, insulin (INS) gene expression ( Table 8.9 ) . In the table, the arrows (i.e., “→”) indicate which transcription factor controls the next transcription factor. In this model, HNF-1α and PDX1 most proximally control insulin ( INS ) gene expression.

Table 8.9

Hierarchy of selected transcription factors that regulate insulin ( INS ) gene expression.

HNF-1 β
v v
v v
INS gene INS gene

Mutations in two enzymes can produce neonatal diabetes: eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3; EIF2A ; chromosome 3q25.1) and homozygous or compound heterozygous loss-of-function mutations in glucokinase (GCK; chromosome 7p13) . Mutations in both EIF2A copies cause Wolcott–Rallison syndrome. In addition to NDM, this rare autosomal recessive disorder displays skeletal dysplasia, retarded growth, and liver disease . EIF2AK3 is required for initiation of translation by facilitating binding of the initiating methronyl transfer tRNA fMet to the 30S ribosomal subunit. GCK serves as the glucose sensor of the β cell . Loss-of-function mutations in GCK cause mildly decreased β cell detection of glucose and subsequent insulinopenia . Women with GCK mutations may exhibit GDM. When both GCK genes are defective, PNDM is the outcome . GCK gene analysis is available commercially.

Novel insulin gene mutations that cause insulin misfolding are detected by the unfolded protein response triggering β cell apoptosis . Because the “abnormal” insulin is not secreted, it is not detected in assays of circulating insulin as are the insulinopathies and the hyperproinsulinemias (see below). The Akita mouse serves as an animal model for this pathogenic mechanism . Defective β cell development may also be a cause (if not the main cause) of “β-cell failure” .

Defects in GLUT2 (encoded by SLC2A2 , solute carrier family 2 member 2; chromosome 3q26.2) cause the Fanconi–Bickel syndrome (FBS) . FBS is manifested as fasting hypoglycemia (because of inadequate release of glucose from hepatocytes) and postprandial hyperglycemia (because of inadequate uptake of glucose by β cells causing insulinopenia and, possibly, reduced hepatic uptake of glucose following a meal) and transient neonatal diabetes . Glycogen accumulated in the renal tubules causes proximal renal tubular dysfunction (i.e., Fanconi syndrome of the tubules) . Glycogen accumulation in the intestinal wall causes epithelial dysfunction potentially manifested as malabsorption and diarrhea.

SLC19A2 (solute carrier family 19 member 2; chromosome 1q24.2) encodes the thiamin transporter protein. Autosomal recessive defects in SLC19A2 cause thiamin-responsive megaloblastic anemia, sensory-neural hearing loss, and diabetes of possible neonatal onset . Thiamin plays a role in several aspects of glucose and intermediary metabolism . The literature does not clearly define why thiamin inborn errors cause diabetes; however, it may relate, in part, to the effect of thiamine pyrophosphate in activating pyruvate decarboxylation via the pyruvate dehydrogenase complex (pyruvate dehydrogenase) .

Wolfram syndrome (WFS; a.k.a.—DIDMOAD: diabetes insipidus; diabetes mellitus, optic atrophy, deafness) results from mutations in WFS1 (Wolframin ER transmembrane glycoprotein; chromosome 4p16.1) . WFS1 helps maintain the endoplasmic reticulum and collaborates in cellular calcium regulation . Diabetes in autosomal recessive WFS1 does not occur in infancy but an autosomal dominant WFS1 form of WFS causes permanent neonatal diabetes .

A variant form of WFS (i.e., WFS2) is caused by CISD2 [cysteine (C), aspartic acid (D), glycine (G), serine/alanine/threonine (S/A/T), histidine (H) (CDGSH); iron-sulfur domain 2; chromosome 4q24] mutations. CDGSH also localizes to the ER. Similarly, CDGSH attaches to an iron/sulfur cluster and, like WFS1, may affect calcium homeostasis. WFS due to WFS2 mutations causes diabetes in childhood but not in neonates .

Mitochondrial diabetes

Mitochondrial mutations (e.g., predominantly the A3243G mutation in tRNA Leu(UUR) ) have been associated with diabetes and deafness (maternally inherited diabetes and deafness, MIDD) as well as more complex syndromes such as MELAS (myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome) and MERRF (myoclonic epilepsy and ragged-red fibers) ( Table 8.10 ) .

Table 8.10

Mitochondrial disorders with possible diabetes.

Disorder Abbreviation mtDNA/nDNA Involved gene/mutation Comment
Chronic progressive external ophthalmoplegia with myopathy CPEO+ mtDNA (or) nDNA Deletions (or) mutations Deletions: Sporadic or maternal inheritance
Mutations in: POLG or RRM2B
PLOG : polymerase gamma (AD)
RRM2B : ribonucleotide reductase regulatory
TP53 inducible subunit M2B (autosome)
Kearns–Sayre syndrome KSS mtDNA Deletion Usually sporadic
Leber hereditary optic neuropathy LHON mtDNA Various mutations Maternal inheritance
Maternally inherited diabetes and deafness MIDD mtDNA MT-TL1 (A3243G) Most common cause of mitochondrial diabetes; maternal inheritance; rare mutations: MT-TK A8296G and MT-TE T14709C
Mitochondrial neurogastrointestinal encephalopathy MNGIE nDNA TYMP Autosomal recessive inheritance; thymidine phosphorylase; an angiogenic factor
Myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome MELAS mtDNA MT-TL1 Maternal inheritance; MT-TLI: most common gene involved; other mutation: T3271C
Myoclonic epilepsy and ragged-red fibers MERRF mtDNA MT-TK Maternal inheritance
or (A8344G)
nDNA PLOG AR inheritance
Pearson syndrome mtDNA Deletion Usually sporadic

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Mar 11, 2021 | Posted by in ENDOCRINOLOGY | Comments Off on Evaluation of hyperglycemia
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