1. Current Concepts of Type 2 DM
林文玉醫師
內科部新陳代謝內分泌科

2. Glucose Tolerance Categories
240
Diabetes
Mellitus
220
200
180
Diabetes
Mellitus
160
140
126
120
IFG
Normal
100
80
Plasma glucose
60
(mg/dL)
IGT
Normal
FPG
2-h PPG (OGTT)

3. mg/dl
mg/d
100 108
144
160 200

4. Pathogenesis of type 2 diabetes:
the triumvirate
Insulin Resistance
DeFronzo R A Diabetes 2009;58:773-795

5. Insulin Resistance
Individuals destined to develop type 2 DM
inherit a set of genes from their parents that
make their tissues resistant to insulin.
The epidemic of diabetes that has enveloped
westernized countries is related to the epidemic
of obesity and physical inactivity.
DeFronzo R A Diabetes 2009;58:773-795

6. Euglycemic Hyperinsulinemic Clamp
A prospective study carried out by Felber and colleages in Lausanne,
Switzerland ( 1990 ).
All subjects had a euglycemic hyperinsulinemic clamp to measure tissue
sensitivity to insulin and OGTT to provide an overall measure of glucose
homeostasis and β-cell function.
The mean plasma glucose and insulin concentration during OGTT were 115
mg/dl and 62 μg/ml, while the mean rate of insulin stimulated glucose
disposal (measured with a 40 mU/m² per min euglycemic insulin clamp )
was 265 mg/m² per minute.
Obesity was associated with 29% decline in insulin sensitivity, but glucose
tolerance remained perfectly normal….With time the obese NGT
individuals progressed to IGT in association with a further 28% reduction in
insulin sensitivity.

7. β-cell fails to compensate
insulin resistance
With time the β-cells cannot continue to produce these very
large amounts of insulin and the obese IGT individuals
progresses to overt diabetes.
The decline in glucose tolerance is associated with a marked
decrease in insulin secretion without further change in insulin
sensitivity.

8. β-cell function
Although the plasma insulin response to the development of insulin
resistance typically increased during the nature history of type 2 dm, this
does not mean that the β-cell is functioning normally.
In SAM and VAGES studies, simply measuring the plasma insulin
response to a glucose challenge does not provide a valid index of β-cell
function.
The β-cell responds to an increment in glucose (ΔG )with an increment in
insulin (ΔI ). Thus the better measure of β-cell function is ΔI/ΔG.
However, the β-cell also is very keenly aware of the body’s sensitivity to
insulin and adjusts its secretion of insulin to maintain normoglycemia.
Thus, the gold standard for measuring β-cell function is the insulin
secretion/insulin sensitivity (ΔI/ΔG ÷IR ).

9. Natural history of type 2 diabetes
DeFronzo R A Diabetes 2009;58:773-795

10. Insulin secretion/insulin resistance (disposition) index (ΔI/ΔG
÷ IR) in individuals with NGT, IGT, and type 2 diabetes
(T2DM) as a function of the 2-h plasma glucose (PG)
concentration in lean and obese subjects.
Losing 2/3 of β-cell function
at 2hr pc 120-140 mg/dl
80-85% loss of β-cell function
at 2hrpc 180-199
DeFronzo R A Diabetes 2009;58:773-795

11. Natural log of the 2-h plasma glucose (PG) concentration
versus natural log of the insulin secretion/insulin
resistance index (measure of β-cell function).
Biomedical phenomena
DeFronzo R A Diabetes 2009;58:773-795

12. Natural History of Type 2 Diabetes
Impaired
glucose tolerance
Undiagnosed
diabetes
Known diabetes
Insulin resistance
Insulin secretion
Postprandial glucose
Fasting glucose
Microvascular complications
Macrovascular complications
Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

13. Pre-diabetes
In the DPP study, individuals with IGT and still had IGT 3 years
later had a 7.9% incidence of background diabetic retinopathy
at study end.
Individuals with IGT progressed to diabetes after 3 years had a
12.6% incidence of BDR.
Their A1cs were between 5.9 and 6.1%.
Peripheral neuropathy in IGT as many as 5-10% individuals.
DeFronzo R A Diabetes 2009;58:773-795

14. mg/dl
mg/d
108
144
200

15. β-cell Failure

16. Pathogenesis of β cell failure
Age ( Aging 1996;8:13-21, J Am geriatrics Soc 1982;30:562-567, Am j Physiol
Endocrinol Metab 2003;284;E7-E12 )
Genes, clusters in families.
– Type 2 diabetes runs in families. In part, this tendency is due to children learning bad
habits — eating a poor diet, not exercising — from their parents. But there is also a
genetic basis. In general, if you have type 2 diabetes, the risk of your child getting
diabetes is 1 in 7 if you were diagnosed before age 50 and 1 in 13 if you were diagnosed
after age 50. Some scientists believe that a child's risk is greater when the parent with
type 2 diabetes is the mother. If both you and your partner have type 2 diabetes, your
child's risk is about 1 in 2. ( from ADA )
– TCF7L2, T-allele of SNP rs7903146 is associated with impaired insulin secretion in vivo
and reduced responsiveness to GLP-1. TCF7L2 encodes for a transcription factor
involved in Wnt signaling, which plays a role in the regulation of β cell proliferation and
insulin secretion.
Insulin Resistance: the precise mechanism remains unknown.

17. Lipotoxicity


Excess deposition of fat ( LC-fatty acyl CoAs, diacylgycerol,
and ceramide ) in liver and muscle has been shown to cause
insulin resistance; deposition of fat in the β cell leads to
impaired insulin secretion and β cell failure.
Elevated plasma FFA levels impair insulin secretion, and this
has been referred to as lipotoxicity.

18. Effect of physiological elevation (48 h) in the plasma FFA concentration
(brought about by lipid infusion) on plasma C-peptide concentration (left)
and insulin secretory response (deconvolution of the palsma C-peptide
curve) (right) in offspring of two type 2 diabetic parents
Impaired first and second phase C-peptide release after intralipid.
Treatment with acipimox ( lower FFA ) improves insulin secretion.
DeFronzo R A Diabetes 2009;58:773-795

19. 

In vitro studies, human pancreas islets were incubated for48h
in the presence of 2mmol/l FFA( oleate-to-palmitate 2:1 ),
insulin secretion , especially the acute insulin response was
markedly reduced. Exposure to FFA caused a marked a
marked inhibition of insulin mRNA expression, glucosestimulated insulin secretion and reduction of islet insulin
content.
PPARr agonist prevented all of these deleterious effects of
FFA.

20. Glucotoxicity

Chronically elevated plasma glucose levels impair β cell function,
and this has been referred to as glucotoxicity.

Rosseti et al: partially pancreatectomized diabetic rats are characterized by
severe defects in both first- and second-phase insulin secretion compared with
control rats. Following treatment with phlorizin, an inhibitor of renal glucose
transport, the plasma glucose profile was normalized, which was associated with
restoration of both first-and second-phases of insulin. 投影片 19


In vitro studies with human islets, similar results.
In rats, elevation of mean day-long plasma glucose concentration
in vivo by as little as 16 mg/dl leads to a marked inhibition of
glucose-stimulated insulin secretion.

22. Six biochemical pathways along which glucose metabolism can form
ROS. Under physiologic conditions, glucose primarily undergoes
glycolysis and oxidative phosphorylation .
Robertson R P J. Biol. Chem. 2004;279:42351-42354

23. The glucotoxic effect on insulin gene
expression via loss of PDX-1 and MafA.
Robertson R P J. Biol. Chem. 2004;279:42351-42354

24. IAPP



Hypersecretion of islet amyloid polypeptide ( IAPP ), which
is co-secreted in a one to one ratio with insulin, can lead to
progressive β cell failure ( in rodents ).
Chavez and colleagues: 150 baboons, 98% homology with
the human genome. Relative amyloid area inversely
correlates with HOMA- β.
Insulin sensitizers leading to a reduction in insulin secretion
would be expected to preserve β -cell function on a longterm base. Rosiglitazone protect human islets against IAPP
toxicity by a PI-3K dependent pathway.

25. INCRETIN EFFECT ON INSULIN SECRETION IN
HEALTHY SUBJECTS
Oral Glucose
Intravenous (IV) Glucose
2.0
C-peptide (nmol/L)
Plasma Glucose (mg/dL)
200
100
0
1.5
Incretin Effect
1.0
0.5
0.0
0
60
Time (min)
120
180
0
60
120
Time (min)
180
N = 6; Mean ± SE; *P≤0.05
Source :Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

26. LOSS OF INCRETIN EFFECT
Control subjects (n=8)
60
Insulin (mU/l)
80
Insulin (mU/l)
80
People with Type 2 diabetes (n=14)
60
Incretin
40
effect
20
40
20
0
0
0
60
120
180
Time (min)
0
60
120
180
Time (min)
Oral glucose load
Intravenous glucose infusion
Source : Nauck et al. Diabetologia. 1986

27. Incretins
GLP-1 and GIP account for 90% of the incretin effect.
In type 2 DM, there is a deficiency of GLP-1 and resistance to the
action of GIP.
The deficiency of GLP-1 can be observed in individuals with IGT
and worsens progressively with progression to T2DM.
Plasma levels of GIP are elevated in T2DM, yet circulating insulin
levels are reduced. This can be interpreted as β-cell resistance to
the stimulatory effect of GIP on insulin secretion.
Tight glycemic control can restore GIP action. Thus β-cell
resistance to GIP is a kind of glucotoxicity.

28. Insulin Resistance in liver





The brain has an obligate need for glucose and is responsible
for~50% of glucose utilization under basal or fasting condition.
The glucose demand is met, most from liver, to lesser extent from
kidney.
During overnight fast, the liver of nondiabetic subjects produces
sugar at the rate of ~2mg/kg per min. In type 2 DM, the rate of
basal HGP is increased , averaging ~2.5 mg/kg per min.
In an average 80 kg person, this amounts to the addition of an
extra 25-30 g of glucose to systemic circulation every night.
The overproduction of glucose by the liver occurs in the presence of
fasting plasma insulin levels that are increased 2.5 to 3.0X,
indicating severe resistance to the suppressive effect of insulin.

29. Basal HGP (left) in control and type 2
diabetic (T2DM) subjects.
DeFronzo R A Diabetes 2009;58:773-795

30. Acceleration of HGP
Increased circulating glucagon levels and enhanced hepatic
sensitivity to glucagon.
Lipotoxicity: leading to increased expression and activity of
phosphoenolpyruvate carboxykinase ( PEP-CK) and pyruvte
carboxylase ( PC ), the rate limiting enzyme for gluconeogenesis.
Glucotoxicity: leading to increased expression and activity of
glucose-6-phosphatase, the rate limiting enzyme for glucose
escape from liver.

31. Insulin Resistance in Muscle
Original workup: euglycemic insulin clamp, tritiated glucose,
femoral arterial and venous catheterization.
Conclusion: muscle insulin resistance could account for over
85-90% of impairment in total body glucose disposal in type 2
DM subjects. The rate of insulin-stimulated glucose disposal
remains 50% less than in normal control subjects.
Impaired glucose transport and phosphorylation, reduced
glycogen synthesis and decreased glucose oxidation.

32. Insulin-stimulated total body glucose uptake (left) and
insulin-stimulated leg glucose uptake (right) in control
(CON) and type 2 diabetic (T2DM) subjects .
DeFronzo R A Diabetes 2009;58:773-795

33. Insulin Signal Transduction
For insulin to work, it must first bind to and then activate the
insulin receptor by phosphorylating key tyrosine residues on β
chain.
This results in the translocation of insulin receptor
substrate( IRS)-1 to the plasma membrane. This leads to the
activation of PI 3-kinase and Akt, resulting in glucose transport
into the cell, activation of NO synthase with arterial vasodilation
and stimulation of multiple intracellular metabolic processes.
The defect in insulin signaling leads to decreased glucose
transport, impaired release of NO with endothelial
dysfunction…

34. In contrast to the severe defect in IRS-1 activation,
mitogen-activated protein ( MAP) kinase pathway, which
can be activated by Shc, is normally responsive to insulin.
Activation of MAP kinase pathway leads to the activation
of a number of intracellular pathways involved in
inflammation, cellular proliferation and atherosclerosis.
This, in part, explains the strong association between
insulin resistance and atherosclerotic disease in nondiabetics and type 2 diabetics.

35. Relationship between impaired insulin signal
transduction and accelerated atherogenesis in insulinresistant subjects, i.e., type 2 diabetes and obesity
?
DeFronzo R A Diabetes 2009;58:773-795

36. There is only one class of oral antidiabetic drugs—TZDs–
that simultaneously augment insulin signaling through IRS1 and inhibit the MAP kinase pathway.
In CHICAGO and PERISCOPE study, pioglitazone halts the
progression of carotid intima-media thickness and coronary
atherosclerosis. PROactive study showed decreased 2nd end
point of death, MI, and stroke by 16%, in pioglitazone group.

37. Hepatic glucose uptake in nondiabetic and diabetic
(DIAB) subjects as a function of plasma glucose and
insulin concentrations and route of glucose
administration
Insulin/Glucagon ratio
DeFronzo R A Diabetes 2009;58:773-795

38. Fat cell (Dysharmonious Quartet )

39. Fat cells in type 2 diabetics are resistant to insulin’s antilipolytic
effect, leading to day-long elevation of FFA.
Dysfunctional fat cell produces excessive pro-inflammatory
adipocytokines and indcing insulin resistance; and fails to secrete
normal amounts of insulin-sensitizing adipocytokines such as
adiponectin.
Enlarged fat cells are insulin resistant, and have diminished
capacity to store fat. When capacity is exceeded, lipid “overflow”
into muscle, liver, and β cells.
Lipid can also overflow into arterial vascular smooth muscles,
leading to acceleration of atherosclerosis.
DeFronzo R A Diabetes 2009;58:773-795

40. Randle Cycle

42. Liver steatosis

43. Effect of lipid infusion to cause a physiologicalpharmacological elevation in plasma FFA concentration on
insulin signal transduction in healthy nondiabetic subjects.
Under steady insulin infusion
DeFronzo R A Diabetes 2009;58:773-795

44. PGC-1( PPAR coactivator 1 )
PGC-1 is the master regulator of mitochondrial biogenesis
and augments the expression of multiple genes involved
inithochondrial oxidative phosphorylation.
Pioglitazone reduced intramyocellular lipid and fatty acyl CoA content was closely related to the improvement in insulinstimulated muscle glucose disposal.
48hr-Lipid infusion, incresing plasma FFA ~1.5 to 2.0X,
inhibited the expression of PGC1α, PGC1 β, PDHA1 and
multiple mitochondrial genes ( oxidative phosphorylation ) in
muscle.

45. GI tract, the incretin effect
(Quntessential Quintet )

46. Hepatic glucose uptake in nondiabetic and diabetic
(DIAB) subjects as a function of plasma glucose and
insulin concentrations and route of glucose
administration
Insulin/Glucagon ratio
Approximately one half of the suppression of HGP following
mixed meal is secondary to inhibition of glucagon secretion,
The other one half is secondary to the increase in insulin secretion
DeFronzo R A Diabetes 2009;58:773-795

47. Incretins

48. Because of its short half-life, native GLP-1 has
limited clinical value
DPP-IV
i.v. bolus GLP-1 (15 nmol/l)
7
9
Val
Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe
37
Ile Ala Trp Leu Val Lys Gly Arg Gly
Intact GLP-1 (pmol/l)
1000
His Ala Glu Gly Thr Phe Thr Ser Asp
Healthy individuals
Type 2 diabetes
500
0
–5 5 15 25 35 45
Time (min)
Enzymatic
cleavage
High clearance
(4–9 l/min)
t½ = 1.5–2.1 minutes
(i.v. bolus 2.5–25.0
nmol/l)
Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

49. GLP-1 enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
•
exenatide
•
liraglutide
Injectables
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
Block DPP-4, the
enzyme that degrades
GLP-1:
• Sitagliptin
• Vildagliptin
• Linagliptin
Oral agents

50. Exenatide Trial
6-h meal tolerance test with double tracer technique (1-14Cglucose orally and 3-3H-glucose IV ) before and after 2 weeks
of exenatide treatment.
Findings: the increment in insulin secretory rate divided by the
increment in plasma glucose increased more than 2X,
demonstrating a potent stimulatory effect of β -cell function.
The increase in insulin secretion, in concert with a decline in
glucagon release, led to a significant reduction in HGP.
Exenatide has no effect on delayed gastric emptying.

51. Alfa cell: role of glucagon
( Setaceous sextet )
The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 1 January 2012

52. Glucagon (pg/ml)
Hyperglucagonemia through-out the day
in people with type 2 diabetes
Time
Time
Reaven et al. J. Clin. Endo. & Metab. 1987

53. Lowered glucose in glucagon receptor knockout mice
Blood glucose (ad lib fed)
***
***
***
5.0
2.5
0.0
700
1000
1600
2000
Time of Day
***
** **
18
Blood Glucose
(mM)
Blood Glucose
(mM)
**
15
6
1000
*
12
9
AUC
1500
10.0
7.5
IP-GTT
**
***
500
0
GR+/+GR-/-
**
**
*
3
0
2400
0
GR+/+
25
50
75
100
125
Time (min)
GR-/-
RW Gelling et al. PNAS 100: 1438-1443, 2003

54. Inhibition of glucagon activity in hGCGR mice. hGCGR mice were dosed with vehicle
(Veh) or Cpd 1 at 15 and 50 mg/kg (mpk) in the same vehicle via an intraperitoneal
injection 1 h before glucagon challenge.
Qureshi S A et al. Diabetes 2004;53:3267-3273

55. Renal Glucose Reabsorption
The kidney filters ~ 162g ( GFR = 180 l/d X fasting
plasma glucose 900 mg/l ) of glucose every day.

56. Targeting the Kidney
Proximal tubule
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

57. SGLT 2 transporter mRNA (left) and protein (middle) and glucose
transport (α-methyl-d-glucopyranoside) (right) are increased in
cultured renal proximal tubular epithelial cells of individuals with type
2 diabetes (T2DM) versus nondiabetic subjects (CON).
DeFronzo R A Diabetes 2009;58:773-795

58. An adaptive response by the kidney to conserve
glucose, which is essential to meet the energy
demands of the body, especially the brain and
other neural tissues, which have obligate need for
glucose, becomes maladaptive in the diabetic
patients.

59. Apple tree to SGLT2i
John R. White, Jr., PA, PharmD CLINICAL DIABETES • Volume 28, Number 1, 2010




In 1835, French chemists isolated a substance, phlorizin, from the bark of apple trees. The
compound was bitter in flavor and reminded them of similar extracts from the cinchona and
willow tree and for a time was referred to as the “glycoside from the bark of apple trees.”
Although the best thinking at the time concluded that phlorizin was a reasonable candidate for
the treatment of fevers, infectious disease, and malaria, within 50 years, it was discovered
that high doses of phlorizin caused glucosuria. Ultimately, it was determined that chronic
administration of phlorizin in the canine model produced many of the same symptoms as
observed in human diabetes (glucosuria, polyuria, and weight loss). Thus, the phlorizininduced diabetes animal model was proposed and utilized in the early 1900s ( Now
Streptozotocin ).
During the next several decades, phlorizin continued to be used in trials evaluating renal
physiology. By the early 1970s, research with phlorizin revealed the location (proximal tubule
brush border) of the active-transport system responsible for glucose reabsorption and that
phlorizin had a much higher affinity for these transporters than did glucose.
There was a resurgence of interest in phlorizin in the late 1980s to early 1990s concurrent with
the characterization of SGLTs and the realization of a potential novel mechanism for reducing
hyperglycemia. Animal studies carried out in 90% pancreatectomized diabetic rats
demonstrated that phlorizin-induced glucosuria normalized fasting and postprandial glucose
levels and reversed insulin resistance. Additionally, phlorizin administration was associated
with reversal of first- and second-phase insulin secretory defects in this model

60. Invokana (canagliflozin)



Invokava™, canagliflozin, is a new once daily alternative for the
maintenance treatment of Type 2 diabetes mellitus.
Canagliflozin is the first and only medication in the class of Sodiumglucose co-transporter 2 (SGLT2) inhibitor.
Usual dose is 100 mg orally once daily initially
 May increase to 300 mg once daily
 Max dose of 100 mg daily is recommended for GFR of 45-59 mL/min


Canagliflozin use may result in increased genitial mycotic infections
Canagliflozin may have a place in therapy as a new third-line agent
after metformin and sulfonylurea failure (possibly in front of DPP-IV
inhibitors like sitagliptin).

61. The brain
Ominous octet

62. 肚子餓很快吃得很急飽得很慢永遠覺得吃很少



Porte and colleagues: insulin was a powerful appetite suppressor. Even
with compensatory hyperinsulinemia, food intake is increased in obese
subjects and type 2 diabetics. That is to say, insulin resistance in
peripheral tissues also extends to the brain.
Functional MRI to localize areas responsible for impaired insulin
regulation. After glucose ingestion, two hypothalamic areas with
consistent inhibition were noted: VM nuclei and paraventricular nuclei
( appetite regulation center ).
The inhibitory response was reduced in obese, insulin resistant, normal
glucose tolerant subjects. And there was a delay in the time taken to
reach maximal inhibitory response.

63. The ominous octet.
DeFronzo R A Diabetes 2009;58:773-795

64. Treatment of type 2 diabetes: a therapeutic
approach based upon pathophysiology.
DeFronzo R A Diabetes 2009;58:773-795

65. Thanks for your Attention