Higher Testosterone Concentrations in Type 2 Diabetic Men Treated with

Metformin

Ajaz Banka , MBBS

Sandeep Dhindsa , MD

Paresh Dandona , MD

Introduction• One third of adult male patients with type 2

diabetes have hypogonadotropic hypogonadism.

• Type 2 diabetes is a common condition affecting over 20 million Americans, it is now an important cause of male hypogonadism.

Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P: Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 89:5462-5468, 2004

Chandel A, Dhindsa S, Topiwala S, Chaudhuri A, Dandona P: Testosterone concentration in young patients with diabetes. Diabetes Care 31:2013-2017, 2008

• Testosterone (T) concentrations in type 2 diabetic men are not related to the glycemic control, duration of diabetes or complications of diabetes.

• Type 2 diabetic men with subnormal T concentrations have higher BMI and waist circumference

Kapoor D, Aldred H, Clark S, Channer KS, Jones TH: Clinical and Biochemical Assessment of Hypogonadism in Men With Type 2 Diabetes: Correlations with bioavailable testosterone and visceral adiposity. Diabetes Care 30:911-917, 2007

• Insulin resistance is negatively associated with T concentrations in men and it is possible that insulin resistance mediates the syndrome of hypogonadotropic hypogonadism in obesity and type 2 diabetes.

Haffner SM, Karhapaa P, Mykkanen L, Laakso M: Insulin resistance, body fat distribution, and sex hormones in men. Diabetes 43:212-219, 1994

• CRP concentrations are widely used in clinical and research settings as a marker of generalized inflammation.

• Inflammation is now known to be a mediator of insulin resistance .

Dandona P, Aljada A, Bandyopadhyay A: Inflammation: the link between insulin resistance,

obesity and diabetes. Trends Immunol 25:4-7, 2004

Purpose of Study

To study the possible effect of glucose lowering agents used in the treatment of type 2 diabetes on T and CRP concentrations in men.

Specifically, we evaluated the effect of

1) Insulin sensitizers, metformin and TZD;

2) Insulin secretagogues, sulfonylureas (SU) and exenatide; and

3) Insulin.

We hypothesized that the use of insulin sensitizers and exenatide is associated with higher T concentrations and lower CRP concentrations.

Methodology

• IRB approval • HIPPA Compliance• Cross-sectional analysis based on retrospective

chart review of 330 consecutive male patients with type 2 diabetes, referred to the center between July 2007 and October 2009.

Inclusion Criteria

Male Patients with Type2 DM.

Exclusion Criteria

• History of panhypopituitarism, • Treatment with T, • Steroids or opiates, patients with foot ulcers,

active infection or those who had a recent surgery or hospitalization for any reason in the last 6 weeks.

Data Collected

Demographic parameters such as age, height, weight.

Data on duration of diabetes, medications,

presence of CHF, malignancies, renal insufficiency, pulmonary disease, stroke, dementia or coronary artery disease were also collected.

Total patients

247

305

25 patients excluded .

208 patients On Metformin

137 patientsOn TZDs

330 T2DM Males

54 patientsnon users

Metformin/TZDs

Statistical Analysis

Group comparisons were carried out by ANOVA, t-tests, Mann-Whitney rank sum tests and chi-square (χ2) tests as appropriate.

Pearson correlation and multiple linear regression analyses between variables were done.

SPSS software (SPSS Inc, Chicago, Illinois) was used for data analysis.

P<0.05 was considered significant.

• Data from 305 men with type 2 diabetes were

analyzed.

Mean Age :58 ± 12 years (range, 26–86 years)

Mean BMI : 34 ± 8 kg/m2 (range, 19–71 kg/m2).

Mean HbA1c : 7.3 ± 1.6% (range, 5–14%).

Duration : 12 ± 8 years (range, 1–46 years).

 

Effect of medications on T concentrations

1. Patients on metformin or TZD had significantly higher TT, FT and BT concentrations and lower prevalence of subnormal FT concentrations as compared to those not on metformin or TZD.

2. Use of insulin secretagogues (SU or exenatide) did not affect T concentrations.

3. Patients treated with insulin also had similar TT, FT and BT concentrations as compared to patients not on insulin .

Effect of medications on CRP concentrations

CRP concentrations were lower in men who were treated with TZD or exenatide .

Use of metformin, insulin or SU did not affect CRP concentrations.

Results

Table 1

Metformin users

TZD users Nonusers of TZD and

metformin

n 208 137 54Age 57 ± 13 59 ± 11 60 ± 13BMI 34 ± 7 34 ± 7 34 ± 7

TT (ng/dl) 391 ± 149** 368 ±140* 310 ± 122

FT (ng/dL) 8.6 ± 2.9** 8.0 ± 2.7* 6.5 ± 2.7

BT (ng/dL) 201 ± 69** 186 ± 63* 155 ± 62

SHBG (nmol/l) 29 ± 16 30 ± 14 30 ± 15

LH (IU/L) 4.9 ± 2.9 5.1 ± 3.0 5.6 ± 4.8

FSH (IU/L) 7.3 ± 5.4* 7.5 ± 6.0* 10.3 ± 9.9% with subnormal

FT23** 33* 53

Charlson index 2.2 ± 1.4** 2.7 ±1.7** 3.4 ± 1.8HbA1c 7.4 ± 1.6 7.3 ± 1.5 7.5 ± 1.8

Duration of diabetes

11 ± 8 13 ± 8 13 ± 9

CRP 4.2 ± 2.5 2.8 ± 1.7** 5.2 ± 3.1

Table 2 SU

Exenatide Nonusers of SU and exenatide

n 146 66 105

Age 59 ± 12 57 ± 9 57 ± 13

BMI 34 ± 7 38 ± 7** 33 ± 6

TT (ng/dl) 361 ± 159 371 ±123 345 ± 133

FT (ng/dL) 8.1 ± 3.0 8.4 ± 2.8 7.8 ± 3.5

BT (ng/dL) 190 ± 70 198 ± 66 183 ± 81

SHBG (nmol/l) 31 ± 17 26 ± 13 28 ± 14

LH (IU/L) 5.3 ± 3.0 5.3 ± 3.6 4.7 ± 2.6

FSH (IU/L) 8.7 ± 6.9 7.4 ± 6.1 7.8 ± 3.0

% with subnormal FT

27 30 33

Charlson index 2.4 ± 1.5 2.5 ±1.5 2.7 ± 1.2

HbA1c 7.3 ± 1.4 7.2 ± 1.3 7.4 ± 1.7

Duration of diabetes

12 ± 7 13 ± 8 12 ± 7

CRP 4.2 ± 2.5 2.8 ± 2.3** 4.5 ± 2.8

Table 3 Insulin users Insulin nonusers

n 201 104

Age 59 ± 12* 56 ± 12

BMI 36 ± 8** 32 ± 6

TT (ng/dl) 356 ± 136 383 ± 161

FT (ng/dL) 7.8 ± 2.8 8.5 ± 3.2

BT (ng/dL) 182 ± 65 199 ± 76

SHBG (nmol/l) 29 ± 17 29 ± 15

LH (IU/L) 5.0 ± 3.7 5.0 ± 2.8

FSH (IU/L) 8.4 ± 7.4 7.1 ± 5.4

% with subnormal FT 36 26

Charlson index 2.9 ± 1.6** 2.1 ± 1.7

HbA1c 7.7 ± 1.7** 6.7 ± 1.0

Duration of diabetes 14 ± 9** 9 ± 7

CRP 4.1 ± 2.8 4.1 ± 2.6

Relation of T and CRP concentrations

CRP concentrations were inversely related to TT (β = -0.40, p<0.001), FT (β = -0.47, p<0.001) and BT (β = -0.34, p<0.001) concentrations, independently of age, BMI, HbA1c, duration of diabetes, Charlson index, presence of congestive heart failure (CHF), chronic kidney disease and anti-diabetic medications.

Limitations

Retrospective chart review analysis.

Selection bias of prescribing these drugs to men who have higher T concentrations to begin with.

Future Directions

• Insulin resistant states in men are associated with low T concentrations, along with low or inappropriately normal LH concentrations. The mechanisms underlying these associations are not known.

Science 22 September 2000: Vol. 289. no. 5487, pp. 2122 - 2125

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

Absence of brain IR expression results in hypothalamic hypogonadism. (A) Epididymi of control and NIRKO mice were removed, and spermatozoa were allowed to diffuse into culture medium. After centrifugation, total epididymal sperm content was determined. (B) Testes and ovaries were removed from control and NIRKO mice and were stained with hematoxylin and eosin. (C) Plasma LH concentrations were determined by radioimmunoassay on serum samples from 6- to 7-month-old mice. (D) Pituitaries were dissected from wild-type and NIRKO mice and stained with polyclonal antibodies to LH. (E) Plasma LH concentrations were determined on serum samples obtained 1 hour after intraperitoneal injection of lupron.

It is possible that insulin resistance at the hypothalamic level contributes to the pathogenesis of this syndrome.

There is no evidence that TZD and metformin directly enhance insulin signaling at the hypothalamic level. It is possible that the effects of TZD and metformin on T concentrations may be mediated via a circulating factor.

Conclusion

• Use of insulin sensitizers is associated with higher T concentrations in type 2 diabetic men.

• TZD and exenatide therapy is associated with lower CRP concentrations.

• These effects need to be confirmed in prospective trials and mechanisms underlying these effects should be explored.

Acknowledgement

• Mentor – Dr. Sandeep Dhindsa– Dr. Paresh Dandona

• Endocrine medicine staff at MF Gates.

• Institutional Review Board

• Dr. Ajay Varanasi• Program Director : Dr Khalid J Qazi.

Thank You!