AC: adenylyl cyclase
 A1c: hemoglobin A1c
 ADA: American Diabetes Association
 BP:

blood pressure
 CHF: congestive heart failure
 CNS: central nervous system
 CSII:
continuous subcutaneous insulin infusion
 CV: cardiovascular
 CVD: cardiovascular
disease
 DPP-4: dipeptidyl peptidase IV
 EPI: epinephrine
 GDM: gestational diabetes
mellitus
 GEF: guanine nucleotide exchange factor
 GFR: glomerular ltration
rate
 GIP: glucose-dependent insulinotropic polypeptide GIRK: G protein–coupled
inwardly rectifying K+ channel GK: glucokinase (hexokinase IV)
 GLP: glucagon-like
peptide
 GLP-1RA: GLP-1 receptor agonist
 GLUT: glucose transporter
 G6P:
glucose-6-phosphate
 GPCR: G protein–coupled receptor
 GRPP: glicentin-related
pancreatic polypeptide
 Hb: hemoglobin
 HbA1c: hemoglobin A1c
 HDL: high-density
lipoprotein
 HGP: hepatic glucose production
 HNF: hepatocyte nuclear transcription
factor
 IAPP: islet amyloid polypeptide
 ICU: intensive care unit
 IFG: impaired
fasting glucose
 IFN: interferon
 IGF-1: insulinlike growth factor 1
 IGT: impaired
glucose tolerance
 IL: interleukin
 IRS: insulin receptor substrate
 Kir: inward rectifying
K+ channel
 LDL: low-density lipoprotein
 MAOI: monoamine oxidase
inhibitor
 MODY: maturity onset diabetes of the young
 mTOR: mammalian target of
rapamycin
 NE: norepinephrine
 NPH: neutral protamine Hagedorn
 NSAID:
nonsteroidal anti-in ammatory drug
 OCT: organic cation transporter
 PC: prohormone
convertase
 PI3K: phosphatidylinositol-3-kinase
 PIP3: phosphatidylinositol 3,4,5-
trisphosphate
 PLC: phospholipase
 PPAR: peroxisome proliferator-activated receptor
SGLT2: sodium-glucose cotransporter 2
 Shc: Src-homology-2-containing
(protein)
 SST: somatostatin
 SUR: sulfonylurea receptor
 TGF: transforming growth
factor
 TNF: tumor necrosis factor

Diabetes mellitus is a spectrum of metabolic disorders arising from myriad pathogenic

mechanisms, all resulting in hyperglycemia. Both genetic and environmental factors
contribute to its pathogenesis, which involves insufficient insulin secretion, reduced
responsiveness to endogenous or exogenous insulin, increased glucose production, or
abnormalities in fat and protein metabolism. The resulting hypergly- cemia may lead to
both acute symptoms and metabolic abnormalities. Major sources of the morbidity of
diabetes are the chronic complica- tions that arise from prolonged hyperglycemia,
including retinopathy, neuropathy, nephropathy, and cardiovascular disease. These
chronic complications can be mitigated in many patients by sustained control of the blood
glucose and treatment of comorbidities such as hyperten- sion and dyslipidemia (Nathan,
2014; Orchard et al., 2015). There are now a wide variety of treatment options for
hyperglycemia that target different processes involved in glucose regulation or
dysregulation (Nathan, 2015).
Physiology of Glucose Homeostasis
Regulation of Blood Glucose
The maintenance of glucose homeostasis, termed glucose tolerance, is a highly developed
systemic process involving the integration of several major organs (Figure 47–1). Although
the actions of insulin are of cen- tral importance, webs of interorgan communication via
other hormones, nerves, local factors, and substrates also play vital roles. e pancreatic β
cell is central in this homeostatic process, adjusting the amount of insu- lin secreted very
precisely to promote glucose uptake a er meals and to regulate glucose output from the
liver during fasting.
In the fasting state (Figure 47–1A), the fuel demands of the body are met by the oxidation
of fatty acids. e brain does not e ectively use fatty acids to meet energy needs and in the
fasting state requires glucose for normal function; glucose requirements are about 2
mg/kg/min in adult humans, largely to supply the CNS with an energy source. Fasting
glucose requirements are primarily provided by the liver. Liver glycogen stores provide
some of this glucose; conversion of lactate, alanine, and glycerol into glucose accounts for
the remainder. e dominant regulation of hepatic glycogenolysis and gluconeogenesis is
controlled by the pancre- atic islet hormones insulin and glucagon. Insulin inhibits hepatic
glucose production, and the decline of circulating insulin concentrations in the
postabsorptive state (fasting) is permissive for higher rates of glucose output. Glucagon
maintains blood glucose concentrations at physiological levels in the absence of
exogenous carbohydrate (overnight and in between meals) by stimulating
gluconeogenesis and glycogenolysis by the liver. Insulin secretion is stimulated by food
ingestion, nutrient absorption, and elevated blood glucose, and insulin promotes glucose,
lipid, and protein anabolism (Figure 47–1B). e centrality of insulin in glucose metabolism
is emphasized by the fact that all the forms of human diabetes have as a root cause some
abnormality of insulin secretion or action.
Pancreatic β cell function is primarily controlled by plasma glucose con- centrations.
Elevations of blood glucose are necessary for insulin release above basal levels, and other
stimuli are relatively ine ective when plasma glucose is in the fasting range (4.4–5.5 mM or
80–100 mg%). ese other stimuli include nutrient substrates, insulinotropic hormones
released from the GI tract, and autonomic neural pathways. Neural stimuli cause some
increase of insulin secretion prior to food consumption. Neural stimula- tion of insulin
secretion occurs throughout the meal and contributes sig- ni cantly to glucose tolerance.
Arrival of nutrient chyme to the intestine leads to the release of insulinotropic peptides
from specialized endocrine cells in the intestinal mucosa. GIP and GLP-1, together termed
incretins, are the essential gut hormones contributing to glucose tolerance. ey are
secreted in proportion to the nutrient load ingested and relay this infor- mation to the
islet as part of a feed-forward mechanism that allows an insulin response appropriate to
meal size. Insulin secretion rates in healthy humans are highest in the early digestive
phase of meals, preceding and limiting the peak in blood glucose. is pattern of
premonitory insulin secretion is an essential feature of normal glucose tolerance.
Mimicking this pattern is one of the key challenges for successful insulin therapy in
diabetic patients.

Elevated circulating insulin concentrations lower glucose in blood by inhibiting hepatic

glucose production (HGP) and stimulating the uptake and metabolism of glucose by
muscle and adipose tissue. Production of glucose is inhibited half-maximally by an insulin
con- centration of about 120 pmol/L, whereas glucose utilization is stimulated half-
maximally at about 300 pmol/L. Some of the e ects of insulin on the liver occur rapidly,
within the rst 20 min of meal ingestion, whereas stimulation of peripheral glucose uptake
may require up to an hour to reach signi cant rates. Insulin has potent e ects to reduce
lipolysis from adipocytes, primarily through the inhibition of hormone-sensitive lipase;
insulin also increases lipid storage by promoting lipoprotein-lipase synthesis and adipocyte
glucose uptake. In muscle and other tissues, insulin stimulates amino acid uptake and
protein synthesis and inhibits protein degradation.
e limited glycogen stores in skeletal muscle are mobilized at the onset of physical activity,
but most of the glucose support for exercise comes from hepatic gluconeogenesis. e
dominant regulation of hepatic glucose production during exercise comes from EPI and
NE. e catecholamines stimulate glycogenolysis and gluconeogenesis, inhibit insulin
secretion, and enhance release of glucagon, all contributing to increased hepatic glucose
output. In addition, catecholamines promote lipolysis, freeing fatty acids for oxidation in
exercising muscle and glycerol for hepatic gluconeogenesis.
Pancreatic Islet Physiology and Insulin Secretion
e pancreatic islets comprise 1%–2% of the pancreatic volume. e pancreatic islet is a
highly vascularized, highly innervated miniorgan containing ve endocrine cell types: α
cells that secrete glucagon, β cells that secrete insulin, δ cells that secrete SST, PP cells
that secrete pancreatic polypeptide, and ε cells that secrete ghrelin.
Insulin is initially synthesized as a single polypeptide chain, preproin- sulin (110 amino
acids), which is processed rst to proinsulin and then to insulin and C-peptide (Figure 47–
2). is complex and highly regulated process involves the Golgi complex, the endoplasmic
reticulum, and the secretory granules of the β cell. Secretory granules are critical in the
cleavage and processing of the prohormone to the nal secretion products, insulin and C-
peptide, and in bringing insulin to the cell membrane for exocy- tosis. Equimolar
quantities of insulin and C-peptide (31 amino acids) are cosecreted. Insulin has a t1/2 of
5–6 min due to extensive hepatic clearance. C-peptide, in contrast, with no known
physiological function or receptor, has a t1/2 of about 30 min. e C-peptide is useful in
assessment of β cell secretion and to distinguish endogenous and exogenous
hyperinsulinemia (e.g., in the evaluation of insulin-induced hypoglycemia). e β cell also
synthesizes and secretes IAPP or amylin, a 37–amino acid peptide. IAPP in uences GI
motility and the speed of glucose absorption. Pramlintide is an agent used in the
treatment of diabetes that mimics the action of IAPP.
Insulin secretion is tightly regulated to provide stable concentrations of glucose in blood
during both fasting and feeding. is regulation is achieved by the coordinated interplay of
various nutrients, GI hormones, pancreatic hormones, and autonomic neurotransmitters.
Glucose, amino acids, fatty acids, and ketone bodies promote the secretion of insulin.
Glucose is the primary insulin secretagogue, and insulin secretion is tightly coupled to the
extracellular glucose concentration. Insulin secretion is much greater when the same
amount of glucose is delivered orally compared to intravenously, a response termed the
incretin e ect and attributed to insulinotropic GI pep- tides. Islets are richly innervated by
both adrenergic and cholinergic nerves. Stimulation of α2 adrenergic receptors inhibits
insulin secretion, whereas β2 adrenergic receptor agonists and vagal nerve stimulation
enhance release. In general, any condition that activates the sympathetic branch of the
auto- nomic nervous system (such as hypoxia, hypoglycemia, exercise, hypo- thermia,
surgery, or severe burns) suppresses the secretion of insulin by stimulation of α2
adrenergic receptors.
e molecular events controlling glucose-stimulated insulin secretion begin with the
transport of glucose into the β cell via GLUT, a facilitative glucose transporter, primarily
GLUT1 in human β cells (Figure 47–3). On entry into the β cell, glucose is quickly
phosphorylated by GK (hexokinase IV); this phosphorylation is the rate-limiting step in
glucose metabolism in the β cell. GK’s distinctive a nity for glucose leads to a marked
increase in glucose metabolism over the range of 5–10 mM glucose, where glucose-
stimulated insulin secretion is most pronounced. e G6P produced by GK activity enters the
glycolytic pathway, producing changes in NADPH and the ratio of ADP/ATP. Elevated
ATP inhibits an ATP-sensitive K+ channel (KATP channel), leading to cell membrane
depolarization. is heteromeric KATP channel consists of an inward rectifying K+ channel
(Kir6.2) and a closely associated protein known as the SUR. Mutations in the KATP
channel are responsible for speci c types of neonatal diabetes and hyperinsulinemic
hypoglycemia. Membrane depolarization following KATP closure leads to opening of a
voltage-dependent Ca2+ channel and increased intracellular Ca2+, resulting in exocytotic
release of insulin from storage vesicles. ese intracellular events are modulated by changes
in cAMP production, amino acid metabolism, and the level of transcrip- tion factors.
GPCRs for glucagon, GIP, and GLP-1 and other regulatory peptides couple to Gs to
stimulate adenylyl cyclase and insulin secretion; receptors for SST and α adrenergic
agonists couple to G to reduce cellular cAMP production and secretion.

e pancreatic α cell secretes glucagon, primarily in response to hypo- glycemia. Glucagon

biosynthesis begins with preproglucagon, which is processed in a cell-speci c fashion to
several biologically active peptides, such as glucagon, GLP-1, and GLP-2 (see Figure 47–
9). In general, gluca- gon and insulin secretion are regulated in a reciprocal fashion; that is,
the agents or processes that stimulate insulin secretion inhibit glucagon secre- tion. Notable
exceptions are arginine and SST: Arginine stimulates and SST inhibits the secretion of both
hormones.

Insulin Action

e insulin receptor is expressed on virtually all mammalian cell types. Tissues that are
critical for regulation of blood glucose are liver, skeletal muscle, fat (Figure 47–1), and
speci c regions of the brain and the pancre- atic islet. e actions of insulin are anabolic, and
insulin signaling is critical for promoting the uptake, use, and storage of the major
nutrients: glucose, lipids, and amino acids. Insulin stimulates glycogenesis, lipogenesis, and
protein synthesis; it also inhibits the catabolism of these compounds. On a cellular level,
insulin stimulates transport of substrates and ions into cells, promotes translocation of
proteins between cellular compartments, regu- lates the action of speci c enzymes, and
controls gene transcription and mRNA translation. Some e ects of insulin (e.g., activation
of glucose and ion transport systems, phosphorylation or dephosphorylation of speci c
enzymes) occur within seconds or minutes; other e ects (e.g., those pro- moting protein
synthesis and regulating gene transcription and cell prolifer- ation) manifest over minutes to
hours to days. e e ects of insulin on cell proliferation and di erentiation occur over a longer
period of time.

The Insulin Receptor

Insulin action is transmitted through a receptor tyrosine kinase that bears functional
similarity to the IGF-1 receptor (Samuel and Shulman, 2016). e insulin receptor is
composed of linked α/β subunit dimers that are products of a single gene; dimers linked by
disul de bonds form a trans- membrane heterotetramer glycoprotein composed of two
extracellular α subunits and two membrane-spanning β subunits (Figure 47–4). e number
of receptors varies from 40/cell on erythrocytes to 300,000/cell on adipocytes and
hepatocytes.

e α subunits inhibit the inherent tyrosine kinase activity of the β sub- units. Insulin binding
to the α subunits releases this inhibition and allows transphosphorylation of one β subunit
by the other and autophosphory- lation at speci c sites from the juxtamembrane region to
the intracellular tail of the receptor. Activation of the insulin receptor initiates signaling by
phosphorylating a set of intracellular proteins, including the IRSs and Shc protein. ese
proteins interact with e ectors that amplify and extend the signaling cascade.

Insulin action on glucose transport depends on the activation of PI3K. PI3K is activated by
interaction with IRS proteins and generates PIP3, which regulates the localization and
activity of several downstream kinases, including PKB (Akt), atypical isoforms of PKC (ς
and λ/τ), and mTOR. e isoform Akt2 appears to control the downstream steps that are
important for glucose uptake in skeletal muscle and adipose tissue and to regulate glucose
production in the liver. Substrates of Akt2 coordinate the translocation of GLUT4 to the
plasma membrane through processes involving actin remodeling and other membrane tra
cking systems. Actions of small G proteins, such as Rac and TC10, have also been
implicated in the actin remodeling necessary for GLUT4 translocation.

GLUT4

GLUT4 is expressed in insulin-responsive tissues such as skeletal muscle and adipose

tissue. In the basal state, most GLUT4 resides in the intra- cellular space; following
activation of insulin receptors, GLUT4 is shi ed rapidly and in abundance to the plasma
membrane (Saltiel, 2016), where it facilitates inward transport of glucose from the
circulation. Insulin signaling also reduces GLUT4 endocytosis, increasing the residence
time of the pro- tein in the plasma membrane (Saltiel, 2016). Following the facilitated dif-
fusion into cells along a concentration gradient, glucose is phosphorylated to G6P by
hexokinases. Hexokinase II is found in association with GLUT4 in skeletal and cardiac
muscle and in adipose tissue. Like GLUT4, hexok- inase II is regulated transcriptionally by
insulin. G6P can be isomerized to G1P and stored as glycogen (insulin enhances the
activity of glycogen synthase); G6P can enter the glycolytic pathway (for ATP production)
and the pentose phosphate pathway.

Pathophysiology and Diagnosis of Diabetes Mellitus

Glucose Homeostasis and the Diagnosis of Diabetes

Broad categories of glucose homeostasis are de ned by the fasting blood glucose or the
glucose level following an oral glucose challenge. ese include the following:

• Normal glucose homeostasis: fasting plasma glucose < 5.6 mmol/L (100 mg/dL)

• Impaired fasting glucose (IFG) : 5.6–6.9 mmol/L (100–125 mg/dL)

• Impaired glucose tolerance (IGT): glucose level between 7.8 and 11.1 mmol/L (140 and
199 mg/dL) 120 min a er ingestion of 75 g liquid glucose solution

• Diabetes mellitus (see Table 47–1)

e American Diabetes Association (ADA) and the World Health Organization (WHO) have
adopted criteria for the diagnosis of diabetes based on the fasting blood glucose, the
glucose value following an oral glucose challenge, or the level of HbA1c (or more simply,
A1c; exposure of