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.

Abstract and Introduction

Abstract

Both type 1 and type 2 diabetes adversely affect the microvasculature in multiple organs. Our understanding of the genesis of this injury and of potential interventions to prevent, limit, or reverse injury/dysfunction is continuously evolving. This statement reviews biochemical/cellular pathways involved in facilitating and abrogating microvascular injury. The statement summarizes the types of injury/dysfunction that occur in the three classical diabetes microvascular target tissues, the eye, the kidney, and the peripheral nervous system; the statement also reviews information on the effects of diabetes and insulin resistance on the microvasculature of skin, brain, adipose tissue, and cardiac and skeletal muscle. Despite extensive and intensive research, it is disappointing that microvascular complications of diabetes continue to compromise the quantity and quality of life for patients with diabetes. Hopefully, by understanding and building on current research findings, we will discover new approaches for prevention and treatment that will be effective for future generations.

Introduction

The cellular elements of the microvasculature appear to be particularly sensitive to injury from sustained hyperglycemia. This injury (and responses by the body directed toward its repair) cause tissue/organ dysfunction that affects the quality and duration of life for persons with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Despite the disparate pathogenesis of these two common forms of diabetes, they (along with secondary forms of diabetes resulting from genetic mutations or pharmaceutical or surgical interventions) all share microvascular injury/dysfunction as a chronic outcome. This scientific statement provides an up-to-date overview of the general pathogenesis of microvascular disease in diabetes, as well as its impact on specific tissues. As such, this statement provides readers with a clear understanding of how microvascular injury adversely affects the normal physiologic function of multiple tissues within the body. This statement does not attempt to provide a compendium of all of the organspecific treatments for limiting microvascular damage that are in use or in development. Nor do we attempt to review/critique the more general systemic approaches to treatment designed to control glycemia, blood pressure (BP), lipids, or oxidative stress.

At the outset, we are reminded that the very diagnosis of diabetes rests on identifying the level of blood glucose that associates with microvascular injury to the eye. In addition, much of the impetus for developing effective glycemic therapy arises from clinical trials that demonstrate that improved glycemic control decreases the incidence and progression of microvascular injury.

The body's microvasculature is a diffuse target whose properties differ considerably between different tissues and organs. The response of the microvasculature to injury/repair likewise differs across tissues and organs. For this reason we chose to use an organbased organizational structure for this scientific statement. However, although we discuss the microvascular complications of diabetes on an organ-by-organ basis, we recognize that in the individual patient all organs are affected simultaneously to a greater or lesser degree (i.e., evident microvascular dysfunction found in one organ is a sentinel of systemic injury, which may be preclinical).

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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