DIABETES MELLITUS

Regulation of blood
glucose
Pancreatic beta cell regulates insulin secretion to
promote glucose uptake after meals and regulate
glucose output from liver during fasting state
NOTES:

In the fasting state, glucose is primarily supplied from the

liver and fatty acids from adipose tissue. At this time
plasma insulin levels are low and plasma glucagon is
increased contributing to increased hepatic
gluconeogenesis and glycogenolysis.

Low insulin levels also releases adipocytes from inhibition

permitting increased lipogenesis. Most tissues oxidize fatty
acids during fasting sparing glucose for use by the CNS.

In the prandial state, nutrient absorption increases plasma

glucose causing an increase in INCRETINS from the gut and
neural stimuli that promote insulin secretion. Liver, skeletal
muscle, and adipose tissue actively take up glucose.
Hepatic glucose production and lipolysis are inhibited and
total body glucose oxidation increases.
 Normal Physiology
During a meal fasting

Increase in plasma  Glucagon elevated

glucose
 Hepatic glycogenolysis
Release of incretins and gluconeogenesis
from gut and neural
stimuli

Liver, skeletal muscle,

adipose tissue take
up glucose
Glucose requirements in
adults is ≈ 2 mg/kg per
minute
 Criteria for diagnosis of
diabetes
Normal Glucose homeostasis : FPG < 5.6 mmol/li
(100 mg/dl)

Impaired Fasting Glucose: 5.6 -6.9 mmol/li (100-

125 mg/dl)

Impaired Glucose Tolerance: Glucose between 7.8

and 11.1 mmol/li (140-199 mg/dl) 120 min after
ingestion of 75 g glucose
 Criteria for diagnosis of
diabetes

Diabetes Mellitus:

symptoms of Diabetes + RBG >11.1 mmol/l (200 mg/dl

FPG >7.0 mmol/l (126mg/dl

2HPG >11.1 mM (200 mg/dl) during an OGTT

Hba1c > 6.5 %

 4 Broad categories of DM

• T1 DM
• T2 DM
• Other forms of DM
• Gestational DM
 Goals of therapy in diabetes
GOAL
INDEX
Glycemic control
A1C <7.0%
Preprandial capillary plasma glucose
3.9-7.2 (70-130mg/dl)
Peak Postprandial capillary plasma glucose
10.0 mmol/L (<180mg/dl
Blood Pressure
<130/80

LDL <2.6 (100 mg/dl)

HDL
>1.1 (>40 mg/dl)
Triglycerides
<1.7 mmol/l (<150 mg/dl)
 Assessment of
Glycemic Control
1. FBS
2. HbA1c
3. SMBG
4. Post-prandial blood sugar
 HbA1c
Indirect measure of glycemic control
LIMITATIONS: hemolytic and other anemias
G6PD deficiency
Recent blood transfusion
Pregnancy
End-stage renal disease
Drugs that stimulate erythropoiesis
 Management of Diabetes

Glycemic control Screen for/manage

 diet/lifestyle Treat associated complication:
 Exercise conditions:  Retinopathy
 medication  Dyslipidemia  CVD
 HPN  Neuropathy
 Obesity  Nephropathy
 CVD  Other complications
 INSULIN ACTION
 Anabolic
 Stimulates/inhibits glycogenesis, lipogenesis,
protein synthesis
 Stimulates transport of substrates & ions into
cells
 Promotes translocation of proteins between
cellular compartments,
 Regulates the action of specific enzymes
 Controls gene transcription & mRNA translation.
NOTES:

Upon entry of glucose into the cell, glucose is

quickly phosphorylated by GLUCOKINASE
producing G-6-P w/c enters the glycolytic pathway.

This increases ATP production w/c inhibits the K

channel leading to cell membrane depolarization.

At the same time the Ca channel opens resulting

in increase intracellular Ca and release of insulin
from storage vesicles. At this time the incretins are
likewise activated stimulating release of insulin.
 SYNTHESIS OF
INSULIN
• Preproinsulin – 110 AA consists of signal peptide, B
chain, C peptide, and A chain.
• Proinsulin –SP is cleaved and S-S bonds form
• PC1 and PC2 (prohormone convertases) cleaves
proinsulin into Insulin
• Insulin and C peptide are stored in granules
 INSULIN
 Stimulates entry of amino acids into the cells
enhancing protein synthesis
 Enhance fat storage ( LIPOGENESIS) and prevents
the mobilization of fat for energy (lipolysis and
ketogenesis)
 Inhibits production of glucose from the liver or
muscle glycogen (glycogenolysis)
 PROINSULIN
 Released in small amounts (3-4%); except in
insulinoma, familial hyperinsulinemia
 Constitutes 10-50% of circulating
immunoreactive insulin content
 Reduced biological action – 2% activity of insulin

 Prolonged circulation time T1/2 = 17 min.

 C - PEPTIDE
• Connecting peptide (joins A and B chains)
• Removed from proinsulin by proteases within
secretory granules
• Released in equimolar amounts with insulin
• Not removed from the circulation by the liver
• Found in higher conc than insulin (4:1)
• Clinically important marker of insulin sec
 INSULIN
 Released in a rapid first phase (insulin
stored in granules and slower second
phase (newly synthesized insulin)
 Significant amount is removed during the
first pass through the liver
 Hepatic insulin levels exceed peripheral
level
 T ½ = 5-6 min
 2 Phases of Insulin
Release
 PHASE 1
 Insulin which has been stored in pancreas
can be released immediately when the BG
starts to rise
 Immediate response bec insulin is premade
and stored
 Brief spike lasting 10 min
 PHASE 2
 Response in insulin action to rising BG
 Slower but longer lasting
 Reaches a plateau in 2-3 hrs

Normally insulin is secreted as basal

(between meals and night time) and meal
Related peaks (1st and 2nd peaks)
 Factors affecting
secretion
Stimulatory Factors Inhibitory Factors
Metabolic Components Decrease cAMP levels
glucose/amino acids/

fatty acids/ketones

Hormonal Components
• Insulin

cyclic AMP - Ca • Epinephrine

growth hormone/ACTH/ • Adrenergic stimulation
Glucagon/cholinergic
• Serotonin
& B adrenergic stim.

Intestinal nutrients

gastrin, secretin,

enteroglucagon, GLP-1
 FUNCTIONS OF
INSULIN
LIVER
o Promotes glucose storage as glycogen
o Induces glucokinase and glycogen
synthase
o Inhibits phosphorylase, inc triglyceride
synthesis, inc VLDL
 SKELETAL MUSCLE
o Increase protein synthesis, inc AA transport,
inc ribosomal protein synthesis
o Increase glycogen synthesis, inc glucose
transport, induces, glycogen synthase, and
inhibits phosphorylase
 ADIPOSE TISSUE
o Increase triglyceride storage

o Induces and activates lipoprotein lipase to

hydrolyze triglycerides from lipoproteins
o Glucose transport provides glycerol
phosphate for esterification of fatty acids
supplied by Lipoprotein transport
 Insulins are
Changing
 1921 bovine and porcine insulin used to
treat humans
 1980’s human insulin available

 1996 insulin analogues

NOTES: Commonly used insulin regimens.

Panel A shows administration of a long-acting insulin

like glargine (detemir could also be used but often
requires twice-daily administration) to provide basal
insulin and a pre-meal short-acting insulin analog.
Panel B shows a less intensive insulin regimen with
BID injection of NPH insulin providing basal insulin and
regular insulin or an insulin analog providing meal-
time insulin coverage. Only one type of shorting-
acting insulin would be used.
Panel C shows the insulin level attained following
subcutaneous insulin (short-acting insulin analog) by
an insulin pump programmed to deliver different basal
rates. At each meal, an insulin bolus is delivered.
B=breakfast; L=lunch; S=supper; HS=bedtime.
Upward arrow shows insulin administration at
mealtime.
Short-Acting Regular Insulin

• Should be injected 30-45 min before

a meal

Short-Acting Insulin Analogs

• Absorbed more rapidly SC
• Rapid increase in plasma insulin conc
and earlier response
• Should be injected <15 min before a
meal
 Long-Acting Insulins
NPH – cloudy, whitish so dissolves gradually
when injected SC; prolonged duration
of action; given either OD or BID w/
short acting insulin
INSULIN ANALOGUES

Insulin Glargine - clear solution; acidic pH;

aggregates in SC space hence;
prolonged absorption;

peakless; exercise does not influence

glargine’s unique absorption kinetics.

Levemir – onset of 1-2 hrs; peaks in 3-9 hrs;

duration of 17-23 hrs.

 Indications for
insulin therapy
 Failure of lifestyle changes and multiple
pharmacological treatments
 Severe weight loss (indicates failure of
orals)
 Severe micro or macrovascular
complications
 Contraindications for orals: pregnancy,
acute stress, liver and kidney disease
 Administration of
Insulin
 RI is given 30-45 min ac

 Short/Rapid acting insulin is given

within 20 minutes or immediately
before meals
 Intermediate acting insulin is usually
given 2/3 in AM and 1/3 in PM
3 Major Components of Exogenous insulin
Therapy

 BASAL INSULIN –
 required to regulate metabolic
processes (gluconeogenesis &
ketogenesis) even in the absence of
meals
 Insulin used as “basal insulin” is
usually intermediate or long acting
 BOLUS OR NUTRITIONAL (MEAL-
RELATED) INSULIN
required to cover glycemic excursions or
other nutritional supplements

Usually given as short (regular or rapid

acting insulin
 Correction Dose Insulin

 Supplemental doses of short or rapid-acting

insulin given to correct elevations in blood
glucose that occur despite the use of basal
and bolus insulin
Insulin Secretagogues and
OHA
 SULFONYLUREAS

First Generation

chlorpropamide (>48 h), tolazamide (12-24h),

Tolbutamide (6-12h)

Second Generation

Glimepiride (24h), Glipizide (12-18h),

Glipizide ER (24h), Glyburide (12-24h)

 MOA of Sulfonylureas

 stimulate insulin release by binding to a

specific site on the B cell K ATP channel
complex and inhibiting its activity
 Reduce hepatic clearance of insulin

 Chronic use causes a decline in insulin

levels but glucose levels are maintained
because chronic hyperglycemia per se
impairs insulin secretion (glucose toxicity)
 NON-SULFONYLUREAS (meglitinides)
 Repaglinide (2-6h)
 Nateglinide (2-4h)
Stimulates insulin release by closing the K
ATP channels; metabolized by the liver
(CYP3A4); also assoc with secondary failure
with chronic use

 GLP-1 AGONIST
exenatide/Liraglutide (4-6h)
 GLUCOSE-LIKE PEPTIDE (GLP- 1 analogues)
Agonists
(Incretin Mimetics)
INCRETIN EFFECT – difference in insulin secretory
response from an oral glucose load compared with IV
glucose administration

INCRETINS – GI hormones released after meals &

stimulate insulin secretion before blood
glucosebecome elevated
- Increases insulin secretion while inhibiting
glucagon release but only when glucose levels
are elevated thus offering the
potential to lower glucose while reducing
possibility of hypoglycemia
- Delays gastric emptying and decreases food
intake
 -Inhibits the release of glucagon by the pancreas.

-Slows glucose absoption into the bloodstream by

reducing the speed at which the stomach empties after
eating, thus making you feel more satisfied after a meal.
 Benefits of incretin
mimetics
Have blood glucose lowering effects which
reduce Hba1c by increasing insulin secretion
and inhibiting glucagon release

Beneficial in weight loss

Exenatide – given SC BID ac; rapidly
absorbed; peaks in 2 hours; cleared by
kidneys; marketed as a pen that delivers 5-10
ug

Liraglutide – given SC od; peaks in 8-12 hrs;

little renal or intestinal excretion; available in a
pen that delivers 0.6, 1.2 and 1.8 mg

ADVERSE EFFECT: nausea and vomiting

Lixenatide (Lyxumia)
Degludec (Tresiba)
 DPP-4 INHIBITORS
 Reduce glucagon and blood glucose levels by
increasing incretin levels ( GLP-1 and GIP)
which inhibit glucagon release thereby
decreasing insulin secretion, gastric emptying
and blood glucose levels.
 Absorbed from the small intestine

 Circulate in unbound form and excreted

unchanged in the urine
 Saxagliptin, vildagliptin, sitagliptin, linagliptin

NOTES: GIP glucose dependent insulinotropic

polypeptide
Inhibition of DPP-4 increases
Active GLP-1
Meal

Intestinal GLP-1 t½ = 1-2

GLP-1 min
release

Active
GLP-1

DPP-4

GLP-1 inactive
(>80% of pool)
GLP-1 Therapeutic Potential in T2DM

 Insulin secretion & biosynthesis

Improves beta cell function

glucagon secretion

gastric emptying, satiety, appetite, 

food intake and weight loss

Beneficial cardiovascular effects

α-GLUCOSIDASE INHIBITORS

 Decreases or delays absorption of glucose in the

GIT by inhibiting the glucosidase in the intestinal
brush border
• Increase the release of glucoregulatory hormone
GLP-1 into the circulation causing drop in glucose
levels
 0.5-0.8 reduction in Hba1c

 Reduce PP glycemia

 GI flatulence, liver function test

 Acarbose, miglitol
 BIGUANIDES
• Increases activity of AMP dependent protein kinase (AMPk)
which stimulates fatty acid oxidation, glucose uptake, and non-
oxidative metabolism and reduses lipogenesis and
gluconeogenesis - inc glycogen storage in skeletal muscle

• Decrease hepatic glucose production

• 1-2% reduction

• Weight neutral

• No hypoglycemia

• Diarrhea, nausea, lactic acidosis

• Metformin
ACTION EXAMPLESHbA1C REDUCTION (%)a
  AGENT-SPECIFIC ADVANTAGES AGENT-SPECIFIC DISADVANTAGES
CONTRAINDICATIONS
Oral             
Biguanidesc
  Hepatic glucose production Metformin 1-2 Weight neutral, Do not cause hypoglycemia,
inexpensiveDiarrhea, nausea, lactic acidosis GFR<50 mL/min, CHF, radiographic contrast studies,
seriously ill patients, acidosis
-Glucosidase inhibitorsc
  GI glucose absorption Acarbose, miglitol0.5-0.8 Reduce postprandial glycemiaGI flatulence,
liver function tests Renal/liver disease
Dipeptidyl peptidase-4 inhibitorsc
  Prolong endogenous GLP-1 action Saxagliptin, sitagliptin, vildagliptin 0.5-1.0 Do not cause
hypoglycemia   Reduce dose with renal disease
Insulin secretagogues – Sulfonylureasc
  Insulin secretion See text and Table 43-8 1-2 Inexpensive Hypoglycemia, weight gain
Renal/liver disease
Insulin secretagogues – Non-sulfonylureasc
  Insulin secretion See text and Table 43-8 1-2 Short onset of action, lower postprandial
glucose Hypoglycemia Renal/liver disease
 TZDs
• Insulin sensitizers that increase insulin- mediated
glucose uptake by 30-50%

• Increase glucose uptake into muscle & adipose tissue

• Increase clearance of fatty acids & reduce lipolysis

• PPARγpromotes uptake of circulating fatty acids into

fat cells and shifts lipid stores from extra adipose to
adipose tse.; increases tse sensitivity to insulin

• Decrease insulin resistance

• 0.5-1.4 reduction in Hba1c

Peripheral edema, CHF, weight gain, fractures,

macular edema, Inc risk for CVD

• Rosiglitazone , pioglitazone
 Oral + Insulin
Combination
 Glycemic control with insulin combination is better
that with insulin alone
 Combination allows use of less insulin injection (ease
of titration and compliance)
 Less weight gain

 Less hypoglycemia
EMERGING THERAPIES FOR DIABETES:

Type 1 DM - immunomodulatory appraches under investigation

that prevent or block autoimmune process
- immune modifying agents such as monoclonal
antibodies against lymphocyte receptors CD 3, CD
20 and CD 25
- immunosuppressant mycophenolate
- immunosuppressive drugs such as cyclosporine,
glucocorticoids, azathioprine

Type 2 DM - SGLT2 inhibitors are highly selective inhibitors of

renal sodium reabsorption and results in glucosuria usually
70-80 g/d at therapeutic doses, increases UTI
- Ex. Canagliflozin, dapagliflozin, empagliflozin
- Can be combined with other drugs inc. insulin
 SGLT2 Inhibitors
Hypoglycemia is rare due to elimination of UGE when
filtered glucose level falls below the transport capacity
of SGLT1 alongside with the compensatory metabolic
changes seen including increased hepatic glucose
production, and the fact that these drugs do not
stimulate insulin secretion.

Not advised when eGFR is <45 mls/min

Weight loss of ~2-3 kg is expected as well as modest

reduction in BP (2-3 mmHg)
 SGLT2 Inhibitors
Adverse effects:
Fungal urogenital infection, increased risk of
bacterial UTI
Adverse effects related to BP reduction like
dizziness and postural hypotension
Rarer side effects:
Diabetic ketoacidosis among T1 DM
Bladder cancer, lower limb amputations
Fournier’s gangrene
 HYPOGLYCEMIA

- Drop in plasma glucose of 70 mg

%
- Sweating, hunger, palpitations,
paresthesias, tremors, anxiety
- Glucagon, epinephrine are
important counter regulatory
hormones
SYMPTOMS AND SIGNS WITH PROGRESSIVE
HYPOGLYCEMIA

BLOOD GLUCOSE mg/dl

70Increases glucagon, epinephrine,

ACTH,
cortisol, and growth hormone

50 palpitation, sweating, dec cognition,

hunger
40 aberrant behavior
30 seizures, coma
20 neuronal cell death
 HYPOGLYCEMIA: Risk Factors

Patient Behavioral &

Characteristics Treatment factors
 Older age  Missed meals

 Female gender  Elevated A!C

 African American heritage  therapy

 Longer duration of
diabetes

 Neuropathy

 Renal impairment

 Previous hypoglycemia
THANK YOU