Time To Complications Occurs in Diabetes

Time to Complications Occurs in Diabetes. Risk Factors Determine When Diabetes Complications Occur

Diabetes causing serious complications is well known. In this study the aim is to follow 950 patients with diabetes for 15 years to study when, in who and how the diabetes complications occurs.

Study Overview

• Status: Terminated
• Conditions: Ischemic Heart Disease; Nephropathy; Diabetic Neuropathy; Vascular Disease; Retinopathy

Detailed Description

Background:

That diabetes cause serious diabetic complications from the eyes, kidneys, nerves and large vessels is known. Good metabolic control during the first 8-10 years has been shown to delay and even alleviate diabetes complications, but not entirely prevent them. When complications occur early after diabetes onset there are also likely genetic causes. If the various diabetes complications have different formation mechanisms or different sensitivity of blood sugar impact is not studied previously.

Hypothesis:

1. Genetic factors determine increased risk of early onset of complications.
2. Oxidative stress increases the risk of complications.
3. Inflammation, hyperlipidemia and hypertension leads to hypoxia and oxidative stress.
4. Combined hypoxia and hyperglycemia leads to complications.

Questionnaires:

1. Are there measurable risk factors that indicate different sensitivity to develop diabetes complications?
2. Are there differences between men and women?
3. Are there differences between type 1 and type 2 diabetes?

Knowledge achievements:

Being able to anticipate and prevent diabetes complications with specific approaches would mean major benefits for patients and society.

Inclusions criteria:

Diabetes type 1, 2 or LADA: 18-75 years of age. Group A: 150 Type 1 Diabetes, duration 15 years (+/- 2 years) and 150 Type 2 Diabetes 2 years (+/- 2 years) (50% K / M) Group B: 150 Type 1 Diabetes, duration 20 years (+/- 2 years) and 150 Type 2 Diabetes 7 years (+/- 2 years) (50% K / M) Group C: 150 Type 1 Diabetes, duration 25 years (+/- 2 years) and 150 Type 2 Diabetes 12 years (+/- 2 years) (50% K / M) Group D: 50 LADA, onset after 35 years of age, duration of 5-10 years (50% K / M)

Follow-up visits:

Group A: After 3, 8 and 13 years Group B: After 5, 10 and 15 years Group C: After 5, 10 and 15 years Group D: After 3, 8 and 13 years

Definitions:

Type 1 Diabetes: Positive ICA-antibodies and/or GAD-antibodies and/or neg C-peptide. Debut <30 years of age.

Type 2 Diabetes: Negative ICA-antibodies and GAD-antibodies and pos C-peptide (> 0.35 mmol/l).

LADA: Positive ICA-antibodies and/or GAD-antibodies. Debut >35 years of age.

Retinopathy: Level of retinopathy based on fundus photography judged by experienced ophthalmologist and classified according to DRP classification in five steps: 1. No retinopathy, 2. Mild non-proliferative retinopathy, 3. Moderate non-proliferative retinopathy, 4. Severe non-proliferative retinopathy, 5. Proliferative retinopathy

ESRD (end stage renal disease): Dialysis or transplantation demanding, GFR (glomerular filtration rate) <10 ml/min.

Overt nephropathy: Albumin excretion at least two consecutive measurements,≥ 300 mg/L and/or S-Creatinine > 100 women and > 110 mmol/l in men.

Incipient nephropathy: Albuminuria between 30 - 300mg/L or Urine albumin/Creatinine >3.

Hypertension: Measured blood pressure in sitting position after 10 minutes rest, at least two consecutive measurements with at least 4 weeks in between, ≥ 130/80.

Hyperlipidemia: ApoA-1/ApoB: >0.5 and/or Triglycerides >1,7 mmol/L and/or LDL >2.5 mmol/L and/or HDL women <1.3, men <1.1 mmol/L and/or cholesterol >4.5 mmol/L.

Heart disease: History of myocardial infarction, angina pectoris and/or ischemic heart disease (file noted). Pharmacological treatment for ischemic heart disease, heart failure or pathological electrocardiographic changes according to Minnesota code.

Cerebrovascular disease: Deemed to have been: if recorded in the patients file and/or if pathological findings demonstrated on CT/MR.

Peripheral vascular disease: Ankle Index <0.9 (blood pressure arm>ankle) Clinical macroangiopathy, (absence of peripheral pulse) or history typical for claudication intermittens.

Neuropathy: Foot investigation: According to international consensus for the investigation and risk assessment of diabetic feet with a view of peripheral autonomic neuropathy (PAN) and peripheral sensory neuropathy (PSN).

• Study Type: Observational
• Enrollment (Actual): 17

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden, 171 76
    • Department of Molecular Medicine and Surgery, Rolf Luft Research centre for Diabetes and Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Typ 1, Typ 2 and LADA Diabetics from the diabetic clinic at Sophiahemmet, Stockholm, Sweden

Description

Inclusion Criteria:

• Diabetes type 1, 2 or LADA: 18-75 years of age.
• Group A: 150 Type 1 Diabetes, duration 15 years (+/-2 years) and 150 Type 2
• Diabetes 2 years (+/-2 years) (50% F/M)
• Group B: 150 Type 1 Diabetes, duration 20 years (+/-2 years) and 150 Type 2
• Diabetes 7 years (+/-2 years) (50% F/M)
• Group C: 150 Type 1 Diabetes, duration 25 years (+/-2 years) and 150 Type 2
• Diabetes 12 years (+/-2 years) (50% F/M)
• Group D: 50 LADA, onset after 35 years of age, duration of 5-10 years (50% F/M)
• Type 1 Diabetes: Positive ICA antibodies and/or GAD-antibodies and/or neg C-peptide. Debut <30 years of age.
• Type 2 Diabetes: Negative ICA-antibodies and GAD-antibodies and pos C-peptide (>0.35 mmol/l).
• LADA: Positive ICA-antibodies and/or GAD-antibodies. Debut >35 years of age.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Group A; 150 Type 1 Diabetes, duration of 15 years (+/- 2 years) and 150 Type 2 Diabetes, duration of 2 years (+/- 2 years) (50% women / men)
Group B; 150 Type 1 Diabetes, duration of 20 years (+/- 2 years) and 150 Type 2 Diabetes, duration of 7 years (+/- 2 years) (50% women / men)
Group C; 150 Type 1 Diabetes, duration of 25 years (+/- 2 years) and 150 Type 2 Diabetes duration of 12 years (+/- 2 years) (50% women / men)
Group D; 50 LADA (Late Autoimmune Diabetes in Adults), debut after 35 years of age, duration of 5-10 years (50% women / men)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to nephropathy	0, 3-5, 8-10 and 13-15 years
Time to autonomous neuropathic ulcers and Amputation	0, 3-5, 8-10 and 13-15 years
Time to peripheral neuropathy	0, 3-5, 8-10 and 13-15 years
Time to peripheral Macro-Vascular Disease, chronic Foot ulcers and Amputation	0, 3-5, 8-10 and 13-15 years
Time to retinopathy	0, 3-5, 8-10 and 13-15 years

Secondary Outcome Measures

Outcome Measure	Time Frame
DNA	0, 3-5, 8-10 and 13-15 years
Endothelial markers	0, 3-5, 8-10 and 13-15 years
Blood lipids	0, 3-5, 8-10 and 13-15 years
CRP	0, 3-5, 8-10 and 13-15 years
Oxidative stress	0, 3-5, 8-10 and 13-15 years
Q10	0, 3-5, 8-10 and 13-15 years
IGFBP-1	0, 3-5, 8-10 and 13-15 years
IGF-1	0, 3-5, 8-10 and 13-15 years
Inflammatory markers	0, 3-5, 8-10 and 13-15 years
Seated blood pressure	0, 3-5, 8-10 and 13-15 years
Pulse	0, 3-5, 8-10 and 13-15 years
Weight	0, 3-5, 8-10 and 13-15 years
BMI	0, 3-5, 8-10 and 13-15 years
Waistlines	0, 3-5, 8-10 and 13-15 years

Collaborators and Investigators

• Sponsor: Karolinska Institutet

Publications and helpful links

General Publications

• Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003 May;26(5):1553-79. doi: 10.2337/diacare.26.5.1553.
• Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol. 2010 Mar 25;316(2):129-39. doi: 10.1016/j.mce.2009.08.018. Epub 2009 Aug 31.
• Penckofer S, Kouba J, Wallis DE, Emanuele MA. Vitamin D and diabetes: let the sunshine in. Diabetes Educ. 2008 Nov-Dec;34(6):939-40, 942, 944 passim. doi: 10.1177/0145721708326764.
• Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, Fowler S; Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005 Apr 19;142(8):611-9. doi: 10.7326/0003-4819-142-8-200504190-00009.
• Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004 Mar;27(3):813-23. doi: 10.2337/diacare.27.3.813.
• Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med. 2008 Feb;121(2):149-157.e2. doi: 10.1016/j.amjmed.2007.09.016.
• Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab. 1994 Sep;79(3):872-8. doi: 10.1210/jcem.79.3.7521354.
• Fullerton B, Jeitler K, Seitz M, Horvath K, Berghold A, Siebenhofer A. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2014 Feb 14;2014(2):CD009122. doi: 10.1002/14651858.CD009122.pub2.
• Gaede P, Pedersen O. Intensive integrated therapy of type 2 diabetes: implications for long-term prognosis. Diabetes. 2004 Dec;53 Suppl 3:S39-47. doi: 10.2337/diabetes.53.suppl_3.s39.
• Genuth S. Insights from the diabetes control and complications trial/epidemiology of diabetes interventions and complications study on the use of intensive glycemic treatment to reduce the risk of complications of type 1 diabetes. Endocr Pract. 2006 Jan-Feb;12 Suppl 1:34-41. doi: 10.4158/EP.12.S1.34.
• Hadi HA, Suwaidi JA. Endothelial dysfunction in diabetes mellitus. Vasc Health Risk Manag. 2007;3(6):853-76.
• Kotronen A, Lewitt M, Hall K, Brismar K, Yki-Jarvinen H. Insulin-like growth factor binding protein 1 as a novel specific marker of hepatic insulin sensitivity. J Clin Endocrinol Metab. 2008 Dec;93(12):4867-72. doi: 10.1210/jc.2008-1245. Epub 2008 Sep 16.
• King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008 Aug;79(8 Suppl):1527-34. doi: 10.1902/jop.2008.080246.
• Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010 Feb;33(2):434-41. doi: 10.2337/dc09-1294. No abstract available.
• Gomes F, Telo DF, Souza HP, Nicolau JC, Halpern A, Serrano CV Jr. Obesity and coronary artery disease: role of vascular inflammation. Arq Bras Cardiol. 2010 Feb;94(2):255-61, 273-9, 260-6. doi: 10.1590/s0066-782x2010000200021. English, Portuguese, Spanish.
• Arai Y, Kojima T, Takayama M, Hirose N. The metabolic syndrome, IGF-1, and insulin action. Mol Cell Endocrinol. 2009 Feb 5;299(1):124-8. doi: 10.1016/j.mce.2008.07.002. Epub 2008 Jul 11.
• Eriksson A, Attvall S, Bonnier M, Eriksson JW, Rosander B, Karlsson FA. Short-term effects of metformin in type 2 diabetes. Diabetes Obes Metab. 2007 Jul;9(4):483-9. doi: 10.1111/j.1463-1326.2006.00624.x.
• Alagona P Jr. Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. Am J Manag Care. 2009 Mar;15(3 Suppl):S65-73.
• Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013 Nov 11;(11):CD008143. doi: 10.1002/14651858.CD008143.pub3.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2012
• Primary Completion (Actual): February 1, 2018
• Study Completion (Actual): February 1, 2018

Study Registration Dates

• First Submitted: September 1, 2009
• First Submitted That Met QC Criteria: September 1, 2009
• First Posted (Estimate): September 2, 2009

Study Record Updates

• Last Update Posted (Actual): August 19, 2022
• Last Update Submitted That Met QC Criteria: August 17, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Diabetes, Complication, Cardio-vascular disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Coronary Disease; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Vascular Diseases; Diabetic Neuropathies
• Other Study ID Numbers: TTCOD