Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini

Disclosures

J Clin Endocrinol Metab. 2017;102(12):4343-4410.

Conclusion

Increasingly we have learned that the microvasculature within different tissues serves multiple functions beyond being a conduit for exchange of respiratory gases, nutrients, and metabolic waste. Consequently, microvascular injury can express common and unique changes at different sites. The dynamic between microvascular injury and repair determines the manifestation of tissuespecific injury. Diabetes affects both injury and repair processes in a manner distinct from other vascular diseases. We have summarized both the general molecular processes involved in diabetic microvascular disease and many of their tissue-specific expressions. Clearly, there is much we still do not understand, and consequently, our ability to successfully intervene to prevent or reverse microvascular disease is quite limited. Insights gained by the use of newer tools, including genetic, proteomic, metabolomics, and other analyses, will certainly add new insights in the basic functioning of microvascular cells, and these insights will light the way to improved therapies.

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Acknowledgments
Weacknowledge science writer Eric Vohr for the contribution to this scientific statement.

Financial Support
S.C.'s contributions were in part supported by NIH P30 AG 049638.

Abbreviations
Aβ, amyloid β; ACCORD, Action to Control Cardiovascular Risk in Diabetes; ACE, angiotensin-converting enzyme; ACEi, angiotensin-converting enzyme inhibitor; AD, Alzheimer's disease; ADP, adenosine 5′-diphosphate; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; AGE, advanced glycation end product; ALA, α-lipoic acid; Ang II, angiotensin II; APC, activated protein C; AR, aldose reductase; ARB, angiotensin II receptor blocker; ATPase, adenosine trisphosphatase; BBB, blood-brain barrier; BK, bradykinin; BK1R, BK1 receptor; BK2R, BK2 receptor; BM, basement membrane; BP, blood pressure; C1-INH, C1-inhibitor; CBF, cerebral blood flow; CI, confidence interval; CKD, chronic kidney disease; CMB, cerebral microbleed; CMI, cerebral microinfarct; CNS, central nervous system; CVD, cardiovascular disease; DAG, diacylglycerol; DCCT, Diabetes Control and Complications Trial; DKD, diabetic kidney disease; DN, diabetic nephropathy; DPN, diabetic peripheral neuropathy; DR, diabetic retinopathy; DSPN, distal symmetric polyneuropathy; DTI, diffusion tensor imaging; ECM, extracellular matrix; EDIC, Epidemiology of Diabetes Interventions and Complications;\eGFR, estimated glomerular filtration rate; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; EPVS, enlarged perivascular space; ER, endoplasmic reticulum; ESKD, end-stage kidney disease; ET-1, endothelin 1; FA, fatty acid; FDG, fludeoxyglucose F18 ligand; FLT-1, fms-like tyrosine kinase 1; GFR, glomerular filtration rate; GLP-1, glucagon-like peptide 1; GSH, glutathione; GWAS, genome-wide association studies; HbA1c, hemoglobin A1c; IAPP, islet amyloid polypeptide; iNOS, inducible NOS; IRS 1/2, insulin receptor substrate 1/2; KD, kidney disease; Keap, Kelch erythroid cell-derived protein with CNC homolog-associated protein; KKS, kallikrein-kinin system; LDL, lowdensity lipoprotein; MAPK, mitogen-activated protein kinase; MRI, magnetic resonance imaging; mRNA, messenger RNA; MTI, magnetization transfer imaging; NAD, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NCV, nerve conduction velocity; NF-κB, nuclear factor κ light chain enhancer of activated B cells; NO, nitric oxide; NOS, nitric oxide synthase; Nrf2, NF-E2–related factor 2; OR, odds ratio; PDGF, platelet-derived growth factor; PET, positron emission tomography; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; QOL, quality of life; RAAS renin-angiotensin aldosterone system; RAGE, receptor for AGE; RAS, reninangiotensin system; RBF, retinal blood flow; RBX, ruboxistaurin; RCT, randomized controlled trial; ROS, reactive oxygen species; RVP, retinal vascular permeability; SHP-1, Src homology-2 domain-containing phosphatase-1; SNP, single-nucleotide polymorphism; STZ, streptozotocin; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGFβ, transforming growth factor β; UKPDS, United Kingdom Prospective Diabetes Study; VEGF, vascular endothelial growth factor; WESDR, Wisconsin Epidemiologic Study of Diabetic Retinopathy; WMH, white matter hyperintensity.

Table 1. Prevalence of Diabetic Retinopathy and Vision-Threatening Diabetic Retinopathy in US Individuals Age 40 and Older
		Crude Prevalence of DR
				Diabetes Population		US Population
Characteristic	N^a	N^b	Weighted Size (in Thousands)^c	95% CI	P Value	95% CI	P Value
Total	1006	324	4202	28.5 (24.9–32.5)		3.8 (3.2–4.5)
Age, years					0.64		<0.001
40–64	575	189	2588	28.0 (23.0–33.6)		3.1 (2.4–3.9)
≥65	431	135	1613	29.5 (25.4–33.9)		6.1 (5.1–7.3)
Sex					0.04		0.046
Male	504	173	2257	31.6 (26.8–36.8)		4.3 (3.5–5.3)
Female	502	151	1944	25.7 (21.7–30.1)		3.3 (2.7–4.1)
Race/ethnicity					0.008		<0.001
Non-Hispanic white	396	107	2507	26.4 (21.4–32.2)		2.9 (2.2–3.9)
Non-Hispanic black	306	119	1006	38.8 (31.9–46.1)		9.6 (7.7–11.9)
Mexican American	197	70	401	34.0 (26.7–42.1)		6.7 (5.4–8.4)
Other	107	28	286	19.7 (12.5–29.7)		3.3 (2.3–4.7)
Crude Prevalence of Vision-Threatening DR
Total	1006	62	655	4.4 (3.5–5.7)		0.6 (0.5–0.8)
Age, years					0.41		0.009
40–64	575	36	376	4.1 (2.8–5.8)		0.4 (0.3–0.7)
≥65	431	26	278	5.1 (3.5–7.3)		1.0 (0.7–1.5)
Sex					0.67		0.81
Male	504	24	298	4.2 (2.8–6.1)		0.6 (0.4–0.9)
Female	502	38	356	4.7 (3.2–6.9)		0.6 (0.4–0.9)
Race/ethnicity					0.006		<0.001
Non-Hispanic white	396	13	304	3.2 (2.0–5.1)		0.4 (0.2–0.6)
Non-Hispanic black	306	28	241	9.3 (5.9–14.4)		2.3 (1.5–3.6)
Mexican American	197	16	85	7.3 (3.9–13.3)		1.4 (0.8–2.7)
Other	107	5	22	1.6 (0.6–3.8)d		0.3 (0.1–0.6)

Data were obtained from the National Health and Nutrition Examination Surveys, 2005 to 2008 (193). Abbreviation: NHANES, National Health and Nutrition Examination Surveys.
^aNumber of participants with diabetes in NHANES, 2005 to 2008.
^bNumber of participants with diabetes who had DR or vision-threatening DR in NHANES, 2005 to 2008.
^cWeighted total number of US adult population who had DR or vision-threatening DR. ^dEstimate is considered unreliable because relative standard error is >30%.

Table 2. Mean Glycosylated Hemoglobin A1c Levels (%) at Each Examination in the Wisconsin Epidemiologic Study of Diabetic Retinopathy, 1980–2013
	Baseline 1980–1982	4-Year 1984–1986	10-Year 1990–1992	14-Year 1994–1996	25-Year 2005–2007	33-Year 2012–2013
Glycosylated hemoglobin A1c, %	10.1	9.4	9.3	8.9	7.6	7.6

Table 3. The Relative Risk for the Prevalence and 4-Year Incidence of Myocardial Infarction, Stroke, and Amputation of Lower Extremities Associated With Presence of Proliferative Diabetic Retinopathy, Adjusted for Age in the Wisconsin Epidemiologic Study of Diabetic Retinopathy
	Myocardial Infarction RR (95% CI)	Stroke RR (95% CI)	Amputation of Lower Extremity RR (95% CI)
T1DM
Prevalence	3.5 (1.5–7.9)	2.6 (0.7–9.7)	7.1 (2.6–19.7)
Incidence	4.5 (1.3–15.4)	1.6 (0.4–5.7)	6.0 (2.1–16.9)
T2DM, taking insulin
Prevalence	0.8 (0.4–1.4)	1.2 (0.6–2.4)	4.2 (2.3–7.9)
Incidence	1.2 (0.5–3.4)	2.9 (1.2–6.8)	3.4 (0.9–13.2)
T2DM, not taking insulin
Prevalence	0.3 (0.0–2.4)	2.9 (0.9–9.4)	5.2 (0.6–45.0)
Incidence	1.5 (0.2–12.5)	6.0 (1.1–32.6)	7.0 (0.8–64.4)

Source: Table 9 from Klein et al. (259). Abbreviation: RR, relative risk.

Table 4. Select Studies Linking Diabetes Complications With Microvascular Complications in the Brain Through Shared Microvascular Mechanisms
Peripheral Microvascular Complication	Shared Microvascular Mechanisms	Brain Outcomes
Peripheral Microvascular Complication	Shared Microvascular Mechanisms	Brain Atrophy	WMH	Infracts	CMBs	Cognitive
Retinopathy	Arteriovenous nicking			Cooper et al. (282)	Qiu et al. (283)	Qiu et al. (284)
	Microhemorrhages			Cooper et al. (282)	Qiu et al. (283)	Qiu et al. (284)
	Venular dilation	Ikram et al. (285)		Cooper et al.; Ikram et al. (282, 285)		Qiu et al. (284)
Nephropathy	Hypertension	Reviewed Beauchet et al. (286)	Verhaaren et al.; King et al. (287, 288)		Reviewed Loitfelder et al. (289)	Reviewed Beauchet et al. (286)
	Creatinine	Rajagopalan et al. (290)		Reviewed Vogels et al. (291)
	Cystatin C	Rajagopalan et al. (290)	(292)			Umemura et al. (293)
	Glomerular filtration rate			Reviewed Vogels et al. (291)		Kurella Tamura et al. (294)
	Islet amyloid polypeptide	Jackson et al. (295)
Neuropathy	Hyperglycemia	Manschot et al.; Launer et al.; Ursache et al. (296–298)	Manschot et al. (298)			Crane et al. (299)
	AGEs, RAGE		Hudson et al. (300)		Hudson et al. (300)
	Vitamin B12 deficiency	Tangney et al. (301)	Feng et al.; de Lau et al.; Tangney et al. (301–303)	Kealey et al. (304)	Tangney et al. (301)	Smith et al. (303)

Unexplored common features in humans include the following: pericyte loss, microvascular reactivity, AGEs, ROS, etc.

Table 5. Distinguishing Characteristics of Mononeuropathies, Entrapment Syndromes, and Distal Symmetrical Polyneuropathy
Feature	Mononeuropathy	Entrapment Syndrome	Distal Symmetric Neuropathy
Onset	Sudden	Gradual	Gradual
Pattern	Single nerve but may be multiple	Single nerve exposed to trauma	Distal symmetrical polyneuropathy
Nerves involved	CN III, VI, VII, ulnar, median, and peroneal	Median, ulnar, peroneal, medial, and lateral plantar	Mixed, motor, sensory, and autonomic

Table 6. Examination: Bedside Sensory Tests
Sensory Modality	Nerve Fiber	Instrument	Associated Sensory Receptors
Vibration	Ab (large)	128 Hz Tuning fork	Ruffini corpuscle mechanoreceptors
Pain (pinprick)	C (small)	Neuro-tips	Nociceptors for pain and warmth
Pressure	Aβ, Aα (large)	1 g and 10 g Monofilament	Pacinian corpuscle
Light touch	Aβ, Aα (large)	Wisp of cotton	Meissner's corpuscle
Cold	Aδ (small)	Cold tuning fork	Cold thermoreceptors

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