• The incidence of diabetes is increasing at an alarming
rate in the US.
– β cells secrete due to high
blood glucose levels
– Glucose uptake into
– α cells secrete when
blood glucose is low
– Glucose is released from
tissues back into blood
• Glucose homeostasis
of pancreas stimulated
to release insulin into
take up more
Blood glucose level
declines to a set point;
stimulus for insulin
and stores it as
Rising blood glucose
level (e.g., after eating
meal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:
skipping a meal)
to release glucagon
into the blood
to the blood
Blood glucose level
rises to set point;
stimulus for glucagon
Normal Glucose Control
• In the post-absorptive period of a normal individual, low basal
levels of circulating insulin are maintained through constant β
cell secretion. This suppresses lipolysis, proteolysis and
glycogenolysis. After ingesting a meal a burst of insulin
secretion occurs in response to elevated glucose and amino
acid levels. When glucose levels return to basal levels, insulin
secretion returns to its basal level.
• Type I DM: Lack of functional β-cells prevents mitigation of
elevated glucose levels and associated insulin responses. The
onset and progression of neuropathy, nephropathy and
retinopathy are directly related to episodic hyperglycemia.
• Type II DM: The pancreas retains some β-cell function but
effective insulin response is inadequate for the glucose level.
Actual insulin levels may be normal or supra-normal but it is
ineffective (insulin resistance).
• Type I
– “Childhood” diabetes
– Loss of pancreatic β cells
– Decreased insulin
• Type II
– “Adult” diabetes
– Defective signal reception in insulin pathway
– Decreased insulin
• Both cause hyperglycemia, glycosuria, lipid breakdown
because tissues are deficient in glucose, ketone bodies
• This is a disease caused by elevated glucose levels
• 2 Types of diabetes:
Type I diabetes (10% of cases)
– Develops suddenly, usually before age 15.
– Caused by inadequate production of insulin because T cell-mediated
autoimmune response destroys beta cells.
– Controlled by insulin injections.
Type II diabetes (90% of cases)
– Usually occurs after age 40 and in obese individuals, but genetics,
aging, and peripheral insulin resistance also.
– Insulin levels are normal or elevated but there is either a decrease in
number of insulin receptors or the cells cannot take it up.
– Controlled by dietary changes and regular exercise.
Type 2 Diabetes: Pathophysiology
HGO Uptake of
Storage In Fat Depots
Inhibition of Lipolysis
Insulin and Oral Hypoglycemics
The peptide hormones directly involved in responding to and controlling
blood glucose levels are located in the islets of Langerhans in the pancreas;
insulin is secreted by β-cells and glucagon by α2 cells. Diabetes is a disorder
of inadequate insulin activity it is associated with episodes of both hyper- and
hypo-glycemia. It is the episodes of hyperglycemia that are associated with
Long term complications
• Diabetes is a
heterogeneous group of
by the elevation of
glucose levels due to a
relative or absolute
deficiency of insulin;
insulin release is
complicated by excess
Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM)
Type 1 DM Type 2 DM
Clinical Onset: <20 years Onset: >30 years
Normal weight Obese
Markedly decreased blood
Increased blood insulin
(early);normal to moderate
decreased insulin (late)
Anti-islet cell antibodies No anti-islet cell antibodies
Ketoacidosis common Ketoacidosis rare;
Genetics 30-70% concordance in twins 50-90% concordance in
Linkage to MHC Class II HLA
No HLA linkage
Linkage to candidate
(PPARγ, calpain 10)
Pathogenesis Autoimmune destruction of β-
cells mediated by T cells and
humoral mediators (TNF, IL-1,
Insulin resistance in
skeletal muscle, adipose
tissue and liver
β-cell dysfunction and
relative insulin deficiency
Absolute insulin deficiency
Islet cells Insulitis early No insulitis
Marked atrophy and fibrosis Focal atrophy and amyloid
β-cell depletion Mild β-cell depletion
The long term complications of diabetes may be
divided into two large groups:
1. Macrovascular: These complications are associated
with pathology of the large and medium-sized vessels;
this includes CHD, stroke, PVD
2. Microvascular: These complications are due to
vascular pathology of the small vessels and include
neuropathy, nephropathy, retinopathy
• Type I: Type 1s depend on exogenous insulin to prevent
hyperglycemia and avoid ketoacidosis. The goal of type 1
therapy is to mimic both the basal and reactive secretion of
insulin in response to glucose levels avoiding both hyper- and
• Type II: The goal of treatment is to maintain glucose
concentrations within normal limits to prevent long term
complications. Weight reduction, exercise (independent of
weight reduction) and dietary modification decrease insulin
resistance and are essential steps in a treatment regimen.
For many this is inadequate to normalize glucose levels, the
addition of hypoglycemic agents is often required, often
insulin therapy is required.
Insulin secretion is regulated by glucose levels, certain amino
acids, hormones and autonomic mediators.
• Secretion is most commonly elicited by elevated glucose
levels; increased glucose levels in β-cells results in increased
ATP levels, this results in a block of K+ channels causing
membrane depolarization which opens Ca2+ channels.
• The influx of Ca2+ results in a pulsatile secretion of insulin;
continued Ca2+ influx results in activation of transcription
factors for insulin.
• Oral glucose elicits more insulin secretion than IV glucose;
oral administration elicits gut hormones which augment the
• Insulin is normally catabolized by insulinase produced by the
Mechanism of Insulin Release in the Pancreas
• Insulin is a peptide hormone synthesized as a
precursor (pro-insulin) which undergoes proteolytic
cleavage to form a dipeptide; the cleaved
polypeptide remnant is termed protein C.
• Both are secreted from the β-cell, normal individuals
secrete both insulin and (but much less) pro-insulin.
• Type 2s are found to secrete high levels of pro-
insulin (pro-insulin is inactive) measuring the level of
C-protein is a more accurate estimation of normal
insulin secretion in type 2s.
• Human insulin consists of 51 aa in
two chains connected by 2
disulfide bridges (a single gene
product cleaved into 2 chains
• T1/2 ~5-10 minutes, degraded by
which cleaves the disulfide links.
• Bovine insulin differs by 3 aas,
pork insulin differs by 1 aa.
• Insulin is stored in a complex with
The synthesis and release of insulin is
1. Glucose (most important),
AAs, FAs and ketone bodies
2. Glucagon and somatostation
3. α-Adrenergic stimulation
inhibits release (most
4. β-Adrenergic stimulation
5. Elevated intracellular Ca2+
promotes release. Insulin secretion - Insulin secretion in beta cells is triggered
by rising blood glucose levels. Starting with the uptake of
glucose by the GLUT2 transporter, the glycolytic
phosphorylation of glucose causes a rise in the ATP:ADP ratio.
This rise inactivates the potassium channel that depolarizes
the membrane, causing the calcium channel to open up
allowing calcium ions to flow inward. The ensuing rise in
levels of calcium leads to the exocytotic release of insulin
from their storage granule.
Mechanism of Insulin Action
• Insulin binds to specific high
affinity membrane receptors with
tyrosine kinase activity
• Phosphorylation cascade results
in translocation of Glut-4 (and
some Glut-1) transport proteins
into the plasma membrane.
• It induces the transcription of
several genes resulting in
increased glucose catabolism and
inhibits the transcription of genes
involved in gluconeogenesis.
• Insulin promotes the uptake of K+
The Goal of Insulin Therapy
Administration of insulins are arranged to mimic the normal
basal, prandial and post-prandial secretion of insulin. Short acting
forms are usually combined with longer acting preparations to
achieve this effect.
Rapid Onset and Ultrashort-acting Preparations
1. Regular insulin: short acting, soluble, crystalline zinc insulin is usually given
subcutaneously; it rapidly lowers glucose levels. All regular insulin is now made
using genetically engineered bacteria; cow and pig no longer used.
2. Lispro, Aspart & Glulisine preparations are classified as ultrashort acting forms
with onset more rapid than regular insulin and a shorter duration. These are less
often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a
meal and has its peak effect 30-90 minutes after injection (vs. 50-120 minutes for
3. Glulisine can be given anywhere from 15 minutes prior to 20 minutes after
beginning a meal.
Intermediate –acting Insulin Preparations
1. Lente insulin: This is a amorphous
precipitate of insulin with zinc ion
combined with 70% ultralente
insulin. Onset is slower but more
sustained than regular insulin. It
cannot be given IV ( this has not
been produced since 2005).
2. Isophane NPH insulin: Neutral
protamine Hagedorn insulin is a
suspension of crystalline zinc insulin
combined with protamine (a
polypeptide). The conjugation with
protamine delays its onset of action
and prolongs it effectiveness. It is
usually given in combination with
Prolonged-acting insulin preparations
1.Ultralente: a suspension of
zinc insulin forming large
particles which dissolve
slowly, delaying onset and
prolonging duration of
Precipitation at the injection
site extends the duration of
action of this preparation.
3. Detemir insulin: has a FA
complexed with insulin
resulting in slow dissolution.
Pump vs. Standard Insulin Therapy
• Insulin Preparations and Treatment
• Various types of insulin are characterized by their
onset and duration of action
• Various premixed
combinations of various
preparations of insulin are
available to ease
combination use should
follow establishment of an
acceptable regime of
Action of Insulin on Various Tissues
Liver Muscle Adipose
↓ glucose production ↑ Glucose transport ↑ glucose transport
↑ glycolysis ↑ glycolysis ↑ lipogenesis&
↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis
↑ Protein synthesis ↑ protein synthesis
Adverse Effects of Insulin
1. Hypoglycemia may occur due to insulin overdose, insufficient
caloric intake (missed meal, improper meal content, delayed
meal, etc.). Ethanol consumption promotes hypoglycemic
response. Symptoms: ↑ HR, diaphoresis, MS changes,
anything (diabetics are usually really good at recognizing
2. Hypokalemia: insulin draws K+ into the cell with glucose
(hyperglycemia with normal K+).
3. Anaphylaxis: when sensitized to non-human insulin gets non-
human insulin (now rare).
4. Lipodystrophy at injection site
5. Weight gain
6. Injection complications
• These agents are useful in the treatment of type 2s
who do not respond adequately to non-medical
interventions (diet, exercise and weight loss).
• Newly diagnosed Type 2s (less than 5 years) often
respond well to oral agents, patients with long
standing disease (often diagnosed late) often require
a combination of agents with or without insulin.
• The progressive decline in β-cell function often
necessitates the addition of insulin at some time in
Type II diabetes. Oral agents are never indicated for
These agents promote the release of insulin
from β-cells (secretogogues); tolbutamide,
glyburide, glipizide and glimepiride.
– These agents require functioning β-cells,
they stimulate release by blocking ATP-
sensitive K+ channels resulting in
depolarization with Ca2+ influx which
promotes insulin secretion.
– They also reduce glucagon secretion and
increase the binding of insulin to target
– They may also increase the number of
• Pharmacokinetics: These agents bind to
plasma proteins, are metabolized in the
liver and excreted by the liver or kidney.
Tolbutamide has the shortest duration
of action (6-12 hrs) the other agents are
effective for ~24 hrs.
Adverse Effects: These agents tend to cause weight
gain, hyperinsulinemia and hypopglycemia. Hepatic
or renal insufficiency causes accumulation of these
agents promoting the risk of hypoglycemia. There
are a number of drug-drug interactions. Elderly
patients appear particularly susceptible to the
toxicities of these agents.
• Tolbutamide is asociated with a 2.5X ↑ in
Onset and Duration
• Short acting: Tolbutamide (Orinase)
• Intermediate acting: Tolazamide (Tolinase),
Glipizide (Glucotrol), Glyburide (Diabeta)
• Long acting: Chloropropamide, Glimerpiride
These agents (repaglinide (Prandin) and nateglinide (Starlix)) act as
• Mechanism: These agents bind to ATP sensitive K+channels like
sulfonylureas acting in a similar fashion to promote insulin
secretion however their onset and duration of action are much
shorter. They are particularly effective at mimicking the prandial
and post-prandial release of insulin. When used in combination
with other oral agents they produce better control than any
• Pharmacokinetics: These agents reach effective plasma levels
when taken 10-30 minutes before meals. These agents are
metabolized to inactive products by CYP3A4 and excreted in bile.
• Adverse Effects: Less hypoglycemia than sulfonylureas; drugs
that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin,
etc.) prolong their duration of effect. Drugs that promote
CYP3A4 (barbiturates, carbamazepine and rifampin) decrease
their effectiveness. The combination of gemfibrozil and
repaglinide has been reported to cause severe hypoglycemia.
Two classes of oral hypoglycemics work by improving insulin target
cell response; the biguanides and thiazolidinediones.
• Metformin is classified as an insulin sensitizer, it increases glucose
uptake and utilization by target tissues. It requires the presence of
insulin to be effective but does not promote insulin secretion. The
risk of hypoglycemia is greatly reduced.
• Mechanism: Metformin reduces plasma glucose levels by
inhibiting hepatic gluconeogenesis. It also slows the intestinal
absorption of sugars. It also reduces hyperlipidemia (↓LDL and
VLDL cholesterol and ↑ HDL). Lipid lower requires 4-6 weeks of
treatment. Metformin also decreases appetite. It is the only oral
hypoglycemic shown to reduce cardiovascular mortality. It can be
used in combination with other oral agents and insulin.
• Adverse effects: Hypoglycemia occurs only when combined with
other agents. Rarely severe lactic acidosis is associated with
metformin use particularly in diabetics with CHF. Drug interactions
with cimetidine, furosemide, nifedipine and others have been
• These agents are insulin
sensitizers, they do not
promote insulin secretion
from β-cells but insulin is
necessary for them to be
and rosigglitazone are
the two agents of this
• Mechanism of Action: These agents act through the activation of peroxisome
proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-γ regulate adipocyte
production, secretion of fatty acids and glucose metabolism. Agents binding to
PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and
skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all
improved. HDL levels are also elevated. Accumulation of subcutaneous fat
occurs with these agents.
• In the liver: ↓glucose output
• In muscle: ↑glucose uptake
• In adipose: ↑glucose uptake , ↓FA release
• Only pioglitazone may be used in combination with insulin; the
insulin dose must be modified. Rosiglitazone may be used with
other hypoglycemic but severe edema occurs when combined with
• Pharmacokinetics: Both are extensively bound to albumin. Both
undergo extensive P450 metabolism; metabolites are excreted in
the urine the primary compound is excrete unchanged in the bile.
• Adverse Effects: Fatal hepatotoxicity has occurred with these
agents; hepatic function must be monitored. Oral contraceptives
levels are decreased with concomitant administration, this has
resulted in some pregnancies.
This enzyme hydrolyses
monosaccharides which are
then absorbed. Acarbose also
inhibits pancreatic amylase. The
normal post-prandial glucose
rise is blunted, glucose levels
rise modestly and remain
slightly elevated for a prolonged
period, less of an insulin
response is required and
hypoglycemia is avoided; use
with other agents may result in
hypoglycemia. Sucrase is also
inhibited by these drugs.
Acarbose and miglitol are two agents of this class used for
type 2 diabetes.
Mechanism of action: These agents are oligosaccharide derivatives
taken at the beginning of a meal delay carbohydrate digestion by
competitively inhibiting α-glucosidase, a membrane bound enzyme
of the intestinal brush border.
Pharmacokinetics: Acarbose is poorly absorbed remaining in the
intestinal lumen. Migitol is absorbed and excreted by the kidney.
Both agents exert their effect in the intestinal lumen.
Adverse Effects: GUESS (flatulence, diarrhea, cramping). Metformin
bioavailability is severely decreased when used concomitantly.
These agents should not be used in diabetics with intestinal
• An easy (and over-
simplified) way to approach
type 2 diabetics is their
“glucostat” is set at a higher
level. Glucagon remains
higher than normal to
maintain the higher glucose
level, but the insulin
response is less
Post Prandial Glucose Regulation
• Incretins are naturally occurring hormones that the gut releases
throughout the day; the level of active incretins increases
significantly when food is ingested.
• Endogenous incretins GLP-1 (glucagon-like peptide 1) and GIP
(glucose-dependent insulinotropic peptide) facilitate the
response of the pancreas and liver to glucose fluctuations
through their action on pancreatic β cells and α cells.
• GIP and GLP-1 are the 2 major incretin hormones in humans: 1
– GIP is a 42-aa peptide derived from a larger protein (ProGIP)
and is secreted by endocrine K cells mainly present in the
proximal gastrointestinal (GI) tract (duodenum and proximal
– GLP-1 is a 30- or 31-aa peptide derived from a larger protein
(proglucagon) and is secreted by L cells located predominantly
in the distal GI tract (ileum and colon). This protein was first
isolated from salivary gland venom of the Gila monster
(investigating how these lizards are able to tolerate long
periods between meals).
These incretins are released from the gut in response to ingestion of
food and collectively contribute to glucose control by:
Stimulating glucose-dependent insulin release from pancreatic beta
cells (GLP-1 and GIP):
Decreasing glucagon production from pancreatic alpha cells (GLP-1)
when glucose levels are elevated.
The combination of increased insulin production and decreased
glucagon secretion reduces hepatic glucose production when plasma
glucose is elevated.
The physiologic activity of incretins is limited by the enzyme
dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active
incretins after their release.
The Incretin Effect Is Diminished in Type 2 Diabetes
Levels of GLP-1 are decreased.
The insulinotropic response to GIP is diminished but not absent.
Defective GLP-1 release and diminished response to GIP may be
important factors in glycemic dysregulation in type 2 diabetes.
Standard vs. Intensive Treatment
Type Glucose Goal HbA1c Goal Treatments BG Monitoring
Normal 110mg/dl 6% ------------ --------------
Standard 225-275 mg/dl 8-9% Insulin BID 2-3 per day
Intensive 150 mg/dl 7% 3 or more 4-6 per day
The trade off between standard and intensive therapy is more frequent
hypoglycemic events (hypoglycemic events, seizures and coma) for a
marked delay in the onset of diabetic complications both microvascular
HbA1c = Hemoglobin A1c is a useful measure of glucose control over the
prior 3-6 months, hyperglycemic episodes result in the nonspecific
glycosylation of various proteins.
• A note on the treatment of hypoglycemia: Oral glucose/carbohydrate
administration results in a more rapid rise in blood glucose than IV
administration; this is due to the involvement of gastrointestinal