HYPOGONADISM IN MEN WITH DM-2 AND

OBESITYMANAV BATRAAssistant Professor of MedicineDivision of Endocrinology and MetabolismState University of New York at Buffalo

DISCLOSURE

■ Speaker Panel – Lilly for Basaglar

■ Physiology of normal testosterone production

■ Association of hypogonadism with DM and obesity

■ Pathophysiology of Hypogonadism associated with

DM and Obesity

■ Effect of Testosterone Replacement on those

pathophysiological changes

■ Our work in this field

Hypothalamus • GnRH

Pituitary • LH, FSH

Leydig and Sertoli cells

• T and Spermatogenesis

Production and Regulation of Testosterone

Pathway of Testosterone Action

TE

STO

STE

RO

NE Amplification

pathwayDHT (Prostate, Skin)

Direct Pathway Muscle

DiverisficationPathway

Estradiol ( Bone,Brain)

Inactivation Pathway

Hepatic oxidation, conjugation , Renal

Excretion

5 alfa

Reductase

(5-10%)

Aromatase

(0.1%)

Pathways of testosterone action; Liu, P. Y. et al. Endocr Rev 2003;24:313-340

TESTOSTERONE

ALBUMIN BOUND

(54-68%)

SHBG BOUND (30-

44)

FREE T (0.5-3%)

Williams Textbook of Endocrinology;12 Edition, Testicular disorders ;Pg 704)

Conditions associated with alterations inSHBG concentrations

Increased SHBG

Decreased SHBG

Bhasin et al, Journal of Clinical Endocrinology & Metabolism, June 2010, Vol. 95(6):2536–2559

HYPOGONADISM

HYPERGONADOTROPIC

Elevated LH and FSH

PRIMARY

HYPOGONADOTROPIC

Low or Inappropriately Normal LH and FSH

SECONDARY

Causes of Hypogonadism

Congenital

Klinefelter syndrome & variants (1/400*)

Kallmann syndrome (1/10,000*)

Hemochromatosis

Acquired

Pituitary disorder

Testicular trauma

Autoimmune syndromes

Medications (corticosteroids,

Ketoconazole, opioids)

Cryptorchidism (8/1000*)

Defects in androgen synthesis or action

Aging

Obesity and Type 2 Diabetes

Severe systemic illness: HIV/AIDS

Chronic renal failure

COPD/Respiratory illness

•Incidence in the male population. Petak SM, et al, 2002 update. Endocr Pract. 2002;8(6):440-456.

Seftel A. et al, Int J Impot Res. 2006;18(3):223-228.

HYPOGONADOTROPIC HYPOGONADISM IN MEN with TYPE 2

DIABETES

Hypogonadism in type 2 diabetic males with erectile dysfunction is hypogonadotropic

Clinical observation: Endocrine workup of male diabetic patients with erectile dysfunction often revealed hypogonadotropic hypogonadism.

Chart review was done of diabetic patients with erectile dysfunction.

50 subjects with low testosterone concentrations were included in the study. Data was collected on LH, FSH and Prolactin concentrations.

43 men had hypogonadotropic (low or normal LH/FSH) hypogonadism and 5 were hypergonadotropic. 2 men had prolactinomas.

Is Diabetes associated with hypogonadism?

Hypogondotropic Hypogonadism in Erectile Dysfunction Associated with Type 2 Diabetes Mellitus: A Common Defect? Tripathy S, Dhindsa S, Garg R,

Khaishagi A, Syed T, Dandona P: Metabolic Syndrome and Related Disorders 1:75-80,2003

Frequent Occurrence of Hypogonadotrophic Hypogonadism in Type 2 Diabetes

■ 103 consecutive, type 2 diabetic male patients

■ Total T (TT), free T by equilibrium dialysis (FT), calculated FT (cFT), and calculated bioavailable T levels (BT) were determined

■ Mean age was 54.7 1.1 years (range, 28-80)

■ Mean BMI was 33.4 0.8 kg/m2 (range, 17.6-63.1)

■ Mean duration of known diabetes was 7.7 0.7 years (range, 0.1-36)

■ 33% had low free testosterone

■ 43.7% had low TT; 36% had low BT

• LH and FSH significantly lower in the hypogonadal group

• Testosterone concentrations were not related to HbA1c, duration of diabetes, complications of diabetes or use of insulin or statins

Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyaya A, Chaudhuri A, Dandona P: Frequent Occurrence of Hypogonadotrophic

Hypogonadism in Type 2 Diabetes. J Clin Endocr Metabol. 2004 Nov;89(11):5462-8.

Hypogonadal Eugonadal

n 34 69

Age(years) 57.2±2.4 53.5±1.5

BMI(kg/m2) 35.7±1.7 31.7±1.0

T (nmol/L) 8.07±0.65 14.58±0.62#

FT(nmol/L) 0.146±0.011 0.306±0.015#

cFT(nmol/L) 0.172±0.007 0.326±0.013#

LH (MIU/mL) 3.15±0.26 3.91±0.24*

FSH (MIU/mL) 4.25±0.45 5.53±0.40*

PRL (MIU/mL) 6.69±0.58 6.69±0.46

SHBG (nmol/L) 28.87±2.79 27.31±1.96

HbA1c% 8.5±0.3 8.42±0.3

Duration of diabetes(years) 9.03±1.31 7.12±0.97

Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyaya A, Chaudhuri A, Dandona P: Frequent Occurrence of

Hypogonadotrophic Hypogonadism in Type 2 Diabetes. J Clin Endocr Metabol. 2004 Nov;89(11):5462-8.

#P<0.001 versus Hypogonadal group *P<0.05 versus Hypogonadal group.

Free Testosterone and BMI in Type 2

DiabetesFree testosterone with BMI and weight

free testosterone (nmol/L)

0.0 0.1 0.2 0.3 0.4 0.5 0.6

BMI (

kg/m

2 ) and

wei

ght (

kg)

0

50

100

150

200

250

weight , r= -0.413, P<0.01

BMI, r= -0.38, P<0.01

Frequent Occurrence of Hypogonadotrophic Hypogonadism in Type 2 Diabetes. Dhindsa S, Prabhakar S, Sethi M,

Bandyopadhyaya A, Chaudhuri A, Dandona P: J Clin Endocr Metabol. 2004 Nov;89(11):5462-8.

Prevalence of low testosterone in lean, overweight and obese diabetic and non-diabetic men

non-diabetic

% o

f men

with

sub

norm

al fr

ee te

stos

tero

ne

0

10

20

30

40

50

60

lean

overweight

obese

diabetic

TESTOSTERONE CONCENTRATIONS IN DIABETIC AND NON-DIABETIC OBESE MEN; Dhindsa S, Miller M, McWhirter C, Chaudhuri A, Ghanim H, Mager D, Dandona P; Diabetes Care, 2010

Several recent studies demonstrate the prevalence

of hypogonadism in diabetic men to be 33% to 50%

Percentage of diabetic men with low and borderline low Bioavailable testosterone (BT) and calculated free testosterone (cFT)

levels per decade. BT <2.5 nmol/l[bar with lines]; BT <4 nmol/l[black]; cFT <0.255 nmol/l[white].

KAPOOR et al: Clinical and Biochemical Assessment of Hypogonadism in men with type 2 Diabetes Mellitus.

Diabetes Care, Volume 30(4).April 2007.911–917

Relation of free testosterone with BMI in diabetic and non-diabetic men

BMI (kg/m2)

0 20 40 60 80 100 120 140

Fre

e T

est

ost

ero

ne

(p

g/m

L)

10

20

30

40

50

60

TESTOSTERONE CONCENTRATIONS IN DIABETIC AND NON-DIABETIC OBESE MEN; Dhindsa S, Miller M, McWhirter C, Chaudhuri A, Ghanim H, Mager D, Dandona P; Diabetes Care, 2010

Non-DM

DM

Comparative Study of Hypogonadism in Type 1 and Type 2 Diabetes

Comparative Study of Hypogonadism in Type 1 and Type 2 Diabetes Tomar et al, Diabetes Care. 2006 May29(5):1120-2.

Type 1

diabetes

Type 2

diabetes

P

(vs type 1

diabetes)

Type 2 DM with

HH

P

(vs type 1

diabetes)

Subjects(n) 50 50 12

Hypogonadal subjects (%) 3 (6%) 13 (26%) 12 (100%)

Age (years) 42.78±1.4 43.74±0.8 0.261 42.85±1.4 0.982

BMI (kg/m2) 26.09±0.75 34.91±1.26 <0.001 37.53±3.7 <0.001

Total T (nmol/L) 22.97±0.99 11.20±0.60 <0.001 6.76±0.65 <0.001

Free Testosterone(nmol/L) 0.382±0.025 0.262±0.022 0.001 0.144±0.021 <0.001

cFT (nmol/L) 0.398±0.019 0.278±0.0.017 <0.001 0.171±0.010 <0.001

Bioavailable T (nmol/L) 9.28±0.44 6.46±0.43 <0.001 4.08±0.19 <0.001

LH (IU/L) 4.12±0.28 3.94±0.33 0.39 2.79±0.37 0.04

FSH(IU/L) 4.46±0.51 5.57±0.61 0.121 3.84±0.52 0.79

Prolactin(mg/L) 11.21±2.1 6.20±0.54 <0.001 5.78±1.13 0.038

SHBG (nmol/L) 49.32±2.83 20.44±1.68 <0.001 20.43±3.54 <0.001

HbA1c% 7.57±0.20 8.40±0.25 0.024 8.95±0.52 0.015

Prevalence of Subnormal Free Testosterone in Type 1 and Type 2 diabetes

0

5

10

15

20

25

30

Type 1 Type 2

%

Comparative Study of Hypogonadism in Type 1 and Type 2 Diabetes Tomar et al, Diabetes Care. 2006 May29(5):1120-2.

Type 1

0 1 2 3

Fre

e T

est

ost

ero

ne

(n

mo

l/l)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Type 2

*

Free Testosterone concentrations in type 1 and type 2 diabetic men between the ages of 18-35 years. *p<0.001; mean age of men with type 1 and type 2 diabetes was 26.45 ± 0.89 and 27.87 ± 0.97 (p=0.37) respectively; mean BMI of men with type 1 and type 2 diabetes was 27.4 ± 1.2 and 38.6 ± 2 (p<0.001) respectively Chandel A, Dhindsa S, Topiwala S, Chaudhuri A, Dandona P: Testosterone Concentrations in Young Patients with Diabetes Mellitus. Diabetes Care, 2008; 31(10):2013-7

Roux-en-Y Gastric Bypass Surgery and Serum Testosterone

Before surgery 2 years after surgery

p

BMI (kg/m2) 46 ± 1 30 ± 1 <0.001

Total Testosterone (ng/dl)

315 ± 201 626 ± 186 <0.001

Calculated Free Testosterone

(ng/dl)

5.8 ± 2.0 10.3 ± 2.0 <0.001

Total Estradiol (ng/dl)

3.8 ± 1.0 3.0 ± 0.7 0.006

22 men (mean age 49 years) underwent Gastric Bypass Surgery and had serum testosterone and estradiol

concentrations re-measured 2 years later. Data are Means ± S.D.

Hammoud et al; JCEM 2009 94:1329-1332

PATHOGENESIS OF HYPOGONADISM IN OBESITY AND TYPE 2 DIABETES

HYPOGONADISM

Insulin Resistance

Inflammatory cytokines

Estradiol

Decreased GnRH Release

Low LH/FSH

0

0.01

0.02

0.03

0.04

0.05

HYPOGONADAL EUGONADAL

0.025

0.045

Free Estradiol by ED

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

HYPOGONADAL(ng/dl) EUGONADAL(ng/dl)

Calculated Free Estradiol

Dhindsa et al: Diabetes Care 34; 1854-1859, 2011

Relation between Free Testosterone and Estradiol Concentrations in Men With Type 2 Diabetes

Dhindsa et al: Diabetes Care 34; 1854-1859, 2011

PATHOGENESIS OF HYPOGONADISM IN OBESITY AND TYPE 2 DIABETES

HYPOGONADISM

Insulin Resistance

Inflammatory cytokines

Estradiol

Decreased GnRH Release

Low LH/FSH

Role of Brain Insulin Receptor in Control of Body Weight and Reproduction: The NIRKO mouse

Bruning JC et al - Science 22 September 2000: Vol. 289. no. 5487, pp. 2122 - 2125

Neuron Specific disruption of IR gene ( NIRKO) mice

Inactivation of IR no impact on brain development

NIRKO mice had impaired spermatogenesis and ovarian follicle

maturation

60% reduction of LH in males and 90 % in females

No alteration in pituitary morphology

Intraperitoneal Injection of Lupron ( GnRH agonist) male mice had

normal increase in LH and female had two fold increase

These data suggest that neuronal expression of IR is essential for

normal regulation of HPG axis.

Summary so far…….

■ Hypogonadotropic hypogonadism is frequent in type 2 diabetes (33%).

■ This syndrome of Hypogonadotropic Hypogonadism is not associated with type 1 diabetes.

■ Obesity is associated with hypogonadism (25%).

■ When morbidly obese men undergo significant weight reduction, testosterone concentrations increase.

■ Hypogonadotropic hypogonadism of type 2 diabetes is not mediated by elevated estradiol concentrations.

Insulin Resistance and Inflammation in

Hypogonadotropic Hypogonadism

and Their Reduction After Testosterone

Replacement in Men with Type 2 DM

Dhindsa et al: Diabetes Care 2016;39: 82-91

■ randomized placebo controlled trial

■ 94 men with type 2 DM , 50 eugonadal, 44 hypogonadal

(HH)

■ Men with HH were randomized to receive intramuscular

T(250 mg) or placebo(1ml saline) every 2 weeks for 24

weeks.

■ Insulin sensitivity was calculated from the glucose infusion

rate (GIR) during the last 30 min of a 4 hour

hyperinsulinemic-euglycemic clamp (80 mU/m2/min) and

expressed as mg/kg lean body mass/min.

■ Fat biopsy was performed on both groups

■ Body composition: Lean mass and fat mass were measured

by DEXA.

■ Sexual Function: Subjects were asked to complete a

questionnaire daily for 7 consecutive days.

■ Total and free testosterone were measured by liquid

chromatography tandem mass spectrometry and

equilibrium dialysis.

Schematic representation of the possible interactions of obesity, inflammation and insulin resistance

Ghanim et al: Role of inflammatory mediators in the suppression of insulin receptor

phosphorylation in circulating mononuclear cells on obese subjectsDiabetologia;2007:50;278 - 285

Hypogonadal Eugonadal p

N 44 50

Age (yrs) 54.6 ± 7.9 51.5 ± 8.9 0.075

BMI (Kg/ m2) 39.8 ± 7.8 34 ± 6.4 <0.001

Total Testosterone

(ng/dl)

252 ± 82 485 ±183 <0.001

Free Testosterone

(ng/dl)

4.4 ± 1.2 7.6 ± 2.2 <0.001

Calculated Free

Testosterone (ng/dl)

5.4 ± 1.1 9.5 ± 1.8 <0.001

SHBG ( nmol/L) 26.3 ± 12.8 36 ± 23.5 0.01

LH (IU/L) 3.9 [2.4,5.8] 5 [3.6,5.1] 0.05

FSH (IU/L) 5.3 [3.5, 9.4] 6.9 [4.2, 9.3] 0.34

Testicular size (ml) 17.4 ± 4.7 19.1 ± 5.3 0.19

Comparison of T2D men with and without HH

Hypogonadal Eugonadal p

PSA (ng/ml) 0.6 [0.4, 0.8] 0.6 [0.4, 1] 0.64

HbA1c % 7 ± 1.1 7.1 ± 1.1 0.66

Trunk Fat Mass by

DEXA (Kg)

28 ± 7 22 ± 8 <0.001

Leg Fat mass (Kg) 12.3 ± 5.1 8.5 ± 3.7 <0.001

Arm Fat mass (Kg) 4.6 ± 1.9 3.2 ± 1.5 <0.001

Total Body sc fat

(Kg)

46 ± 14 34 ± 12 <0.001

Visceral Fat (L) 8.22 ± 3.24 5.96 ± 2.53 0.001

Hepatic Fat (L) 5.77 ± 6.93 7.1 ± 7.8 0.43

Total Lean Mass (Kg

)

71 ± 11 64 ± 9 0.002

Comparison of T2D men with and without HH

0

2

4

6

8

10

12

14

16

GIR (mg/kg lean mass/min) GIR adjusted for age and fat mass

p=0.15

*p=0.002

HYPOGONADAL

EUGONADAL

INSULIN RESISTANCE in MEN with HH and T2D

mRNA expression of insulin signaling mediators in

adipose tissue

IR IRS-1 GLUT-4 AKT-2

mR

NA

Exp

ress

ion

(Arb

itrar

y U

nits

)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

Eugonadal

Hypogonadal

*

**

*

Basal protein levels of IR-b subunit and Akt-2 in

adipose tissue

IR-b AKT-2

Pro

tein

Imag

e D

ensi

tom

etry

(rel

ativ

e to

act

in)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Eugonadal

Hypogonadal

*

*

Testosterone (N = 20) Placebo (N = 14)

0 week 24 week p 0 week 24 week p

BMI (Kg/m2) 39+ -7.6 38.9+ -8.1 0.73 39.4+ -7.9 40.6+ -8.4 0.22

Total testosterone 259+ -85 561+ -183 < 0.001 239+ -81 280 + -132 0.08

Free testosterone 4.5 ± 1.3 13.8 ± 4.1 <0.001 4.2± 1.2 5.1 ± 1.7 0.07

Total estradiol 30.1 ±17.2 62.6 ±42.7 0.01 26.1 ±8.3 26.4 ±10.6 0.92

Testosterone (N = 20) Placebo (N = 14)

0 week 24 week p 0 week 24 week pTrunk

subcutaneous fat mass

27.2±8.1 25.3±7.3 0.03 26.7± 6.9 27.2± 7.9 0.36

Arm fat mass4.5± 2.1 4.4±1.9 0.48 4.4±2 5.1 ± 1.9 0.04

Leg fat mass 11.8± 4.5 11.2± 4.5 0.28 12.3± 6.7 11.9 ± 5.2 0.55

Total-body subcutaneou

s fat44.5± 13.7 42.1±12.5 0.02 44.5± 15 45.4 ±14.4 0.11

Visceral fat 7.81 ±3.03 7.25 ± 2.86 0.40 7.33 ±2.73 7.44± 3.18 0.61

Hepatic fat % 6.17 ± 6.454.41 ± 3.80 0.22 3.93± 6.06 3.39 ± 4.06 0.55

Arm Lean Mass

8.1± 1.3 8.8 ± 1. 3 0.01 7.9± 1.5 8.4 ± 1.8 0.08

Leg lean mass 21. 6 ± 3.2 22.5± 3.20.07

21.2± 4.3 20.9± 3.1 0.74

Total Body Lean mass

70.6± 9.2 73.2± 10.70.001

69.1± 13.4 68.3± 13 0.41

Effect of Testosterone on insulin resistance in men with Type 2 Diabetes and Hypogonadotropic Hypogonadism

0

2

4

6

8

10

12

14

Testosterone Placebo

0 week

24 weeks

*p=0.004

Glu

cose infu

sio

n r

ate

mg/k

g lean m

ass/m

in

Increase in insulin sensitivity by 36%; p=0.03 as compared to placebo

IR IRS-1 GLUT-4 Akt-2

Ch

an

ge i

n m

RN

A E

xp

ressio

n (

%)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

180

190

200Baseline

Testosterone

Placebo

*#

*# *#*#

Change in mRNA expression of insulin signaling mediators in adipose

tissue following 24 weeks of Testosterone or placebo treatment

IR-b Akt-2

Perc

en

t ch

an

ge i

n p

rote

in l

evels

(%

)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160 Baseline

Testosterone

Placebo

*#

*#

Percent change in protein levels of IR-b subunit and AKT-2 in adipose tissue

following 24 weeks of testosterone or placebo treatment.

PTP-1B TLR-4 JNK-1

Ch

an

ge

in

mR

NA

Exp

ressio

n (

%)

0

10

20

30

40

50

60

70

80

90

100

110

120

130 Baseline

Testosterone

Placebo

*# *#

Percent change in mRNA expression in adipose tissue following 24 weeks of

testosterone or placebo

PTP-1B

Pe

rcen

t c

han

ge

in

pro

tein

le

vels

(%

)

0

10

20

30

40

50

60

70

80

90

100

110

120

130Baseline

Testosterone

Placebo

*#

Percent change in protein levels of PTP-1-B in adipose tissue

following 24 weeks of T or placebo

SOCS-3 IKK-b PTEN

Ch

an

ge i

n m

RN

A E

xp

ressio

n i

n M

NC

(%

)

0

10

20

30

40

50

60

70

80

90

100

110

120

130 Baseline

Testosterone

Placebo

*#*#

*#

Percent change in mRNA expression in mononuclear cells following 24

weeks of testosterone or placebo treatment.

SOCS-3

Pe

rcen

t c

han

ge

in

pro

tein

le

vels

(%

)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140Baseline

Testosterone

Placebo

*#

Percent change in protein levels of SOCS-3 in MNC following 24 weeks

of testosterone or placebo treatment

Change in serum FFA and Leptin after 6 months of testosterone or placebo

Weeks

3 15 24

Ch

an

ge

in

pla

sm

a F

FA

(m

M)

-0.30

-0.25

-0.20

-0.15

-0.10

-0.05

0.00

0.05

0.10

Placebo

Testosterone

*#

*#

Weeks

3 15 24

Ch

an

ge i

n p

lasm

a L

ep

tin

(n

g/m

l)

-6.5

-6.0

-5.5

-5.0

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0Placebo

Testosterone

*#*#

Change in serum CRP and TNF-α after 6 months of testosterone or placebo

Weeks

3 15 24

Ch

an

ge

in

pla

sm

a C

RP

(m

g/L

)

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

Placebo

Testosterone

*#

*#

Weeks

15 24

Ch

an

ge

in

pla

sm

a T

NF

- (

pg

/ml)

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2Placebo

Testosterone

*#*#

* P < 0.05 by t-test

Eugondal vs. Hypogonadal T2DM Expression of Androgen and

Estrogen Receptors and Aromatase in Adipose tissue.

AR ER Aromatase

mR

NA

Ex

pre

ssio

n (

Arb

itra

ry U

nit

s)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Eugonadal

Hypogonadal

*

*

*

* P < 0.05 by paired t-test vs. baseline

# P< 0.05 by t-test vs. placebo

Change in Expression of Androgen and Estrogen Receptors

and Aromatase in Adipose tissue of Hypogonadal T2DM men

Treated with Testosterone or placebo for 6 Months

AR ER-a Aromatase

Ch

an

ge

in

mR

NA

Ex

pre

ssio

n i

n A

dip

ose t

issu

e (

%)

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170Baseline

Testosterone

Placebo

*# *#

*#

* P < 0.05 by t-test

Basal mRNA Expression of Androgen Receptor in MNC of

Eugondal and Hypogonadal T2DM men

mRNA Protein

AR

mR

NA

Ex

pre

ssio

n (

Arb

itra

ry U

nit

s)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

Eugonadal

Hypogonadal

*

* P < 0.05 by paired t-test vs. baseline

# P< 0.05 by t-test vs. placebo

Change in mRNA and protein Expression of Androgen Receptor in

MNC of Hypogonadal T2DM men following Testosterone or placebo

treatment for 6 Months

Weeks

3 15 25

Ch

an

ge i

n A

R p

rote

in i

n M

NC

(%

)

-20

-10

0

10

20

30

40

50

Placebo

Testosterone

*

*#

Weeks

3 15 25Ch

an

ge i

n A

R m

RN

A E

xp

res

sio

n i

n M

NC

(%

)

-20

-10

0

10

20

30

40

50

60

Placebo

Testosterone

*#

*#

■ Hypogonadotropic hypogonadism is frequent in type 2 diabetes (33%).

■ This syndrome of Hypogonadotropic Hypogonadism is not associated with type 1 diabetes.

■ This Functional defect is probably mediated by insulin resistance.

■ Testosterone treatment in these men has insulin sensitizing and anti inflammatory effects in addition to reduction in adiposity and increase in lean body mass

■ This effect is probably due to increase in expression of genes related to insulin signalling transduction and supression of genes interfering with action of insulin

ACKNOWLEDGEMENT

Dr Dandona

Dr Dhindsa

Dr Ghanim

Research Staff

Jean – Research Nurse

Kelly - Lab Technician

THANK YOU