Current concept of type 2 DM

Current Concepts of Type 2 DM

林文玉醫師內科部新陳代謝內分泌科

Glucose Tolerance Categories

FPG 2-h PPG (OGTT)

126

60

80

100

120

140

160

180

200

Plasma glucose(mg/dL)

Normal

Diabetes Mellitus

240

220

Diabetes Mellitus

Normal

IGT

IFG

108mg/dl

144mg/d 200160

100

Pathogenesis of type 2 diabetes: the triumvirate

DeFronzo R A Diabetes 2009;58:773-795

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.


Insulin Resistance

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.

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.

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 ).

Natural history of type 2 diabetes


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.


80-85% loss of β-cell function

at 2hrpc 180-199

Losing 2/3 of β-cell function

at 2hr pc 120-140 mg/dl

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

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Natural History of Type 2 Diabetes

Macrovascular complicationsMicrovascular complications

Insulin resistanceInsulin resistance

ImpairedImpairedglucose toleranceglucose tolerance

UndiagnosedUndiagnoseddiabetesdiabetes Known diabetesKnown diabetes

Insulin secretionInsulin secretion Postprandial glucose

Fasting glucoseFasting glucose

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.


108mg/dl

144mg/d 200

β-cell Failure

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.

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.

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.

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, glucose-stimulated insulin secretion and reduction of islet insulin content.

PPARr agonist prevented all of these deleterious effects of FFA.

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.

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

The glucotoxic effect on insulin gene expression via loss of PDX-1 and MafA.

Robertson R P J. Biol. Chem. 2004;279:42351-42354

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 long- term base. Rosiglitazone protect human islets against IAPP toxicity by a PI-3K dependent pathway.

INCRETIN EFFECT ON INSULIN SECRETION IN HEALTHY SUBJECTS

Oral Glucose Intravenous (IV) Glucose

N = 6; Mean ± SE; *P0.05Source :Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498.

C-p

ep

tid

e (

nm

ol/

L)

Time (min)

0.0

0.5

1.0

1.5

2.0

Incretin EffectIncretin Effect

Pla

sm

a G

luc

os

e (

mg

/dL

)

200

100

0

Time (min)

60 120 180060 120 1800

Oral glucose load

Intravenous glucose infusion

Time (min)In

sulin

(m

U/l)

80

60

40

20

0

18060 1200

Time (min)

Insu

lin (

mU

/l)

80

60

40

20

0

18060 1200

IncretinIncretin

effecteffect

Control subjects (n=8)Control subjects (n=8) People with Type 2 diabetes (n=14)People with Type 2 diabetes (n=14)

LOSS OF INCRETIN EFFECT

Source : Nauck et al. Diabetologia. 1986

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.

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.

Basal HGP (left) in control and type 2 diabetic (T2DM) subjects.


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.

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.

Insulin-stimulated total body glucose uptake (left) and insulin-stimulated leg glucose uptake (right) in control

(CON) and type 2 diabetic (T2DM) subjects .


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…

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 non-diabetics and type 2 diabetics.

Relationship between impaired insulin signal transduction and accelerated atherogenesis in insulin-

resistant subjects, i.e., type 2 diabetes and obesity


?

There is only one class of oral antidiabetic drugs—TZDs– that simultaneously augment insulin signaling through IRS-1 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.

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

Fat cell (Dysharmonious Quartet )

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.


Randle Cycle

Liver steatosis

Effect of lipid infusion to cause a physiological-pharmacological elevation in plasma FFA concentration on insulin signal transduction in healthy nondiabetic subjects.


Under steady insulin infusion

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 Co-A content was closely related to the improvement in insulin-stimulated 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.

GI tract, the incretin effect(Quntessential Quintet )

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

Incretins

Because of its short half-life, native GLP-1 has limited clinical value

7

37

9

Lys

DPP-IV

His Ala Thr Thr SerPheGlu Gly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Type 2 diabetes

Healthy individuals

i.v. bolus GLP-1 (15 nmol/l)

Inta

ct G

LP-1

(pm

ol/l)

Time (min)

–5 5 15 35 450

500

1000

25

t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l)

Enzymatic cleavage

High clearance (4–9 l/min)

Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

GLP-1 enhancementGLP-1 enhancement

Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

GLP-1 secretion is impaired in Type 2 diabetesGLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-lifeNatural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life:

• exenatide

• liraglutide

Injectables

Block DPP-4, the enzyme that degrades

GLP-1:• Sitagliptin• Vildagliptin• Linagliptin

Oral agents

Exenatide Trial

6-h meal tolerance test with double tracer technique (1-14C-glucose 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.

Alfa cell: role of glucagon( Setaceous sextet )

The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 1 January 2012

Hyperglucagonemia through-out the day in people with type 2 diabetes

Reaven et al. J. Clin. Endo. & Metab. 1987

Time Time

Glu

ca

go

n (

pg

/ml)

Lowered glucose in glucagon receptor knockout mice

700 1000 1600 2000 24000.0

2.5

5.0

7.5

10.0

******

*****

Time of Day

Blo

od

Glu

cose

(mM

)

GR-/-

GR+/+

RW Gelling et al. PNAS 100: 1438-1443, 2003

Blood glucose (ad lib fed)

0 25 50 75 100 125

0

3

6

9

12

15

18

**

*******

***

** *

Time (min)

Blo

od

Glu

cose

(mM

) GR+/+GR-/-0

500

1000

1500

***

AU

C

IP-GTT

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

Renal Glucose Reabsorption

The kidney filters ~ 162g ( GFR = 180 l/d X fasting plasma glucose 900 mg/l ) of

glucose every day.

Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

Targeting the Kidney

Proximal tubule

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).


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.

Apple tree to SGLT2i

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 phlorizin- induced 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

John R. White, Jr., PA, PharmD CLINICAL DIABETES • Volume 28, Number 1, 2010

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 Sodium-glucose 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).

The brainOminous octet

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.

The ominous octet.


Treatment of type 2 diabetes: a therapeutic approach based upon pathophysiology.


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Current concept of type 2 DM