CHRONIC COMPLICATIONS IN CHRONIC COMPLICATIONS IN DIABETES MELLITUS DIABETES MELLITUS CPT Thomas Oliver, M.D. CPT Thomas Oliver, M.D. Endocrinology, Diabetes and Endocrinology, Diabetes and Metabolism Service Metabolism Service Walter Reed Army Medical Walter Reed Army Medical Center Center
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MAJOR DETERMINING FACTORSMAJOR DETERMINING FACTORS
DurationDuration
Glycemic ControlGlycemic Control
Type 1 vs. Type 2Type 1 vs. Type 2
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1 DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
726 within 5 years of onset = 0 comp’s726 within 5 years of onset = 0 comp’s
Comparison of intensive therapy vs.... Comparison of intensive therapy vs....
conventional therapyconventional therapy
Mean follow-up 6.5 years (4-9) with 98% Mean follow-up 6.5 years (4-9) with 98%
data collectiondata collection
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
DCCT RESULTS:DCCT RESULTS: In Intensive GroupIn Intensive Group:: Retinopathy progressed by 3 steps in Retinopathy progressed by 3 steps in
70.3% fewer patients.70.3% fewer patients. Initial appearance of retinopathy was Initial appearance of retinopathy was
reduced by 27%.reduced by 27%. Need for laser photocoagulation reduced Need for laser photocoagulation reduced
by 56%. by 56%.
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 1 - GLYCEMIC CONTROL IN TYPE 1
DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 2 - GLYCEMIC CONTROL IN TYPE 2DM COMPLICATIONSDM COMPLICATIONS - GLYCEMIC CONTROL IN TYPE 2 - GLYCEMIC CONTROL IN TYPE 2
DCCT looked at Type 1 DCCT looked at Type 1 onlyonly!! Can we apply findings to type 2?Can we apply findings to type 2? Studies:Studies:
Small Japanese study with 110 patients Small Japanese study with 110 patients shows results similar to DCCT.shows results similar to DCCT.
Metformin monotherapy showed significant Metformin monotherapy showed significant benefit on:benefit on: Cardiovascular diseaseCardiovascular disease Diabetes-related deathDiabetes-related death All cause mortalityAll cause mortality
So So HOWHOW does diabetes damage blood does diabetes damage blood vessels?vessels?
Best understood mechanism is by non-Best understood mechanism is by non-enzymatic glucosylation (glycation) of proteins enzymatic glucosylation (glycation) of proteins and other macromolecules. and other macromolecules.
Other mechanisms postulated include changes Other mechanisms postulated include changes in NADP+ and NADH levels associated with in NADP+ and NADH levels associated with
alternative glucose metabolic fatesalternative glucose metabolic fates when when usual pathways are saturated.usual pathways are saturated.
Chronic hyperglycemia causes Chronic hyperglycemia causes increased glycation of proteins, increased glycation of proteins, resulting in resulting in AAdvanced dvanced GGlycation lycation EEndproducts (ndproducts (AGEAGEs)s)
These can cause damage through loss These can cause damage through loss of function, turning on/off signal of function, turning on/off signal pathways within cells, or alteration in pathways within cells, or alteration in gene expression.gene expression.
One of the proteins which is glycated One of the proteins which is glycated is Hemoglobin. Because it is found in is Hemoglobin. Because it is found in the blood, it is convenient to measure the blood, it is convenient to measure as HgA1c.as HgA1c.
Because RBCs (and thus Hg) survive Because RBCs (and thus Hg) survive in the blood for 90-120 days, the in the blood for 90-120 days, the HgA1c provides a means to assess HgA1c provides a means to assess glycemic control over this period.glycemic control over this period.
The Role of InsulinThe Role of Insulin Hyperglycemia causes complicationsHyperglycemia causes complications Insulin causes complicationsInsulin causes complications
Type 1 Type 1 Usually not hyperinsulinemic; therefore Usually not hyperinsulinemic; therefore
concentrate on controlling hyperglycemia.concentrate on controlling hyperglycemia. Type 2 (Actively under investigation)Type 2 (Actively under investigation)
Unclear whether increasing insulin to achieve Unclear whether increasing insulin to achieve normal sugars overall benefit!!! normal sugars overall benefit!!!
Quiescent StageQuiescent Stage End of Proliferative changes; vision End of Proliferative changes; vision
usually stable at whatever level of loss usually stable at whatever level of loss was sustained during proliferative phase.was sustained during proliferative phase.
Laser photocoagulationLaser photocoagulation seems to seems to accelerate transition from proliferative accelerate transition from proliferative phase to quiescent phase. Intent is to phase to quiescent phase. Intent is to arrive at quiescent phase with minimal arrive at quiescent phase with minimal loss of vision.loss of vision.
Macular EdemaMacular Edema In DM, retinal vessels are more permeable.In DM, retinal vessels are more permeable. Fluid leakage from vessels to retina can Fluid leakage from vessels to retina can
cause localized edema.cause localized edema. If present in the macula, can cause If present in the macula, can cause
reduction in VA (20/20 > 20/50).reduction in VA (20/20 > 20/50). Affects 300,000 pts/year.Affects 300,000 pts/year. Risk can be decreased with laser rx.Risk can be decreased with laser rx.
To To B B (for biopsy) or not to (for biopsy) or not to BB Not needed in typical cases (~ 80%)Not needed in typical cases (~ 80%)
DM > 10 yearsDM > 10 years Other “opathies” presentOther “opathies” present Gradual progressionGradual progression
Helpful in atypical casesHelpful in atypical cases Within 10 yrs. onset of DMWithin 10 yrs. onset of DM Other indicators of inflammatory processOther indicators of inflammatory process Rapid ProgressionRapid Progression
Dietary Protein RestrictionDietary Protein Restriction 0.6-0.8 gm/kg/day in established 0.6-0.8 gm/kg/day in established
macroalbuminuria or falling GFRmacroalbuminuria or falling GFR Glycemic ControlGlycemic Control Regular Monitoring for NephropathyRegular Monitoring for Nephropathy Avoid Nephrotoxins (NSAIDs, some abx)Avoid Nephrotoxins (NSAIDs, some abx)
Increased Risk (independent of HTN, etc.)Increased Risk (independent of HTN, etc.) Worsened neurologic injuries/deficitsWorsened neurologic injuries/deficits
Diabetic EncephalopathyDiabetic Encephalopathy Subtle cognitive defects Subtle cognitive defects Possible increased risk from repeated Possible increased risk from repeated
episodes of severe hypoglycemiaepisodes of severe hypoglycemia CNS infections - MucormycosisCNS infections - Mucormycosis
Prevention StrategiesPrevention Strategies Glycemic ControlGlycemic Control Smoking CessationSmoking Cessation Regular Sensory ExamsRegular Sensory Exams Personal ProtectionPersonal Protection Consider RevascularizationConsider Revascularization Aggressive Treatment and Follow-Up of Aggressive Treatment and Follow-Up of