Diabetic microvascular complications: possible targets for improved macrovascular outcomes

Figures & data

Table 1 Advancing treatment approaches in type 1 diabetes in 1993–1995

A. Diabetes control and complications trial

Multiple insulin injections were found to be associated with a lower incidence of diabetic nephropathy, retinopathy, and neuropathy

B. Captopril trial

Angiotensin-converting enzyme inhibitor was found to decrease the rate of loss of renal function, using the time to doubling of serum creatinine

C. Pulsatile insulin study^Citation14

Control of high and low blood glucose in type 1 diabetic patients was found to be improved beyond use of the DCCT protocol 7 days/week by use of the DCCT protocol 6 days/week + intravenous infusions of insulin in pulses 1 day/week. Each patient was his/her own control. This study did not address long-term complications

D. Orthostatic hypotension^Citation15

Improved lifestyle with stabilization of locomotion through diminution of this neurological complication when pulsatile insulin was added 1 day/week to the DCCT protocol 6 days/week. Each patient was his/her own control

E. Hypertension^Citation16

Lower doses of antihypertensives required during 3-month rotations of the pulsatile infusion 1 day/week were added to the DCCT protocol 6 days/week

Abbreviation: DCCT, Diabetes Control and Complications Trial.

Table 2 Human studies: effects of nonhemodynamic angiotensin mechanisms

References	Drug/patient	Primary endpoint	Comment
Persson et al^Citation10	Irbesartan Type 2 diabetes	Inflammatory markers decreased a. IL-6 b. C-reactive protein c. Fibrinogen	Albuminuria decreased
Flammer et al^Citation44	Losartan versus atenolol Type 2 diabetes and hypertension	a. Flow-mediated vasodilation decreased b. 8-Isoprostane decreased with losartan, but not atenolol	8-Isoprostane is generated from membrane phospholipid by free radicals
Kramer et al^Citation45	Losartan Hypertension, no diabetes	a. Platelet aggregation decreased after 8 h b. Endothelial cells (human)AT2-induced PDGF2-α + thromboxane blocked by incubation with EXP3179	Losartan metabolites: EXP3174 uses AT2 receptor EXP3179 no receptor Metabolism of losartan requires 8 h
Fortuno et al^Citation46	EXP3179 or losartan (but not EXP3174), irbesartan or quinapril, no diabetes	Human phagocytic mononuclear cells: a. NADPH oxidase b. Protein kinase C expression inhibited	Expression of matrix metalloproteinase inhibited
Furumatsu et al^Citation11	Enalapril, losartan, and spironolactone, no diabetes	Albuminuria decreased over 1 year	Urine type 4 collagen decreased
Mehdi et al^Citation12	Lisinopril, spironolactone diabetes a. Type 2: 80% b. Type 1: 20%	Albuminuria decreased over 1 year

Table 3 Pulsatile insulin study: baseline¹⁷

A. Randomized trial of DCCT protocol (control) versus DCCT protocol 6 days/week + pulsatile insulin (infusion group)   1 day/week in type 1 diabetic patients with proteinuria, effect on progression of loss of renal function as measured by Ccreat Seventy-one patients seen every week Distribution: control (n = 34), infusion (n = 37) B. ACE inhibitors preferred for blood pressure control Forty-five patients Distribution: control (n = 25) infusion (n = 20) Distribution: no ACE inhibitors: control (n = 9) infusion (n = 17), P = ns C. Blood pressures (mmHg) by 24-h ambulatory method not significantly different at baseline, 52 weeks, and 78 weeks
Baseline	Infusion group (n = 37)	Control group (n = 34)	P value
Systolic	133.6 ± 3.2	132.5 ± 2.6	0.79
Diastolic	77.8 ± 1.5	79.6 ± 1.7	0.44
52 weeks	Infusion group (n = 37)	Control group (n = 34)	P value
Systolic	136.0 ± 2.7	133.2 ± 2.6	0.46
Diastolic	76.9 ± 1.8	78.7 ± 1.9	0.50
Baseline	Infusion group (n = 23)	Control group (n = 26)	P value
Systolic	134.8 ± 4.7	134.5 ± 3.1	0.96
Diastolic	78.3 ± 1.8	80.4 ± 2.1	0.46
78 weeks	Infusion group (n = 23)	Control group (n = 26)	P value
Systolic	131.6 ± 3.8	135.1 ± 3.4	0.49
Diastolic	74.7 ± 1.8	78.8 ± 2.2	0.17

Notes: Slopes of loss of Ccreat not significantly different at 52 weeks (n = 71); significantly different at 78 weeks (n = 49); did not change when the graph was drawn from 52 to 78 weeks.

Table 4 Pulsatile insulin infusion: impact of ACE inhibition

A. Normal population Average rate of loss of Ccreat ∼1 mL/min/year B. Type 1 diabetic nephropathy patients Prior to 2000 ∼15–25 mL/min/year Addition of pulsatile insulin to DCCT protocol No ACE inhibition Control group loss = 5.3 mL/min/year Infusion group loss = 5.2 mL/min/year With ACE inhibition Control group (n = 25) ∼8 ± 1 mL/min/year (52 weeks = 7.1; 78 weeks = 8.9 mL/min/year) Infusion group (n = 20) ∼0.8 ± 0.2 mL/min/year (52 weeks = 0.96; 78 weeks = 0.60 mL/min/year) P values: unpaired t-test: 52 weeks <0.11; 78 weeks <0.02 Wilcoxon rank sum test: 52 weeks <0.20; 78 weeks <0.01 C. Mean arterial pressure for patients with highest slope of loss of Ccreat baseline, endpoint DCCT protocol (control group, n = 10) 93.1 ± 2.3, 94.8 ± 3.1 mmHg Pulsatile IV (infusion group, n = 10) 91.8 ± 2.0, 91.3 ± 2.5 mmHg D. Mean arterial pressure for patients with lowest slope of loss of Ccreat baseline, endpoint DCCT protocol (control group, n = 10) 103.1 ± 3.0, 109.9 ± 2.9 mmHg* Pulsatile IV (infusion group, n = 10) 100.7 ± 2.1, 99.9 ± 2.8 mmHg*

Note:

* P < 0.05.

Table 5 Pulsatile insulin study: cardiac and autonomic neuropathic studies

A. Objective measures of autonomic nervous system function Heart rate variability (HRV) not different for DCCT protocol (control group at Joslin) versus pulsatile insulin (infusion group at Joslin) Combining study groups at Joslin Patients with early cardiac autonomic neuropathy: Significant fall in glycohemoglobin A1c at 3, 6, and 12 months Several measures in the time and frequency domains indicated improved parasympathetic function^Citation25 Patients with advanced cardiac autonomic neuropathy: significant fall in A1c at 6 months only. No measures of HRV changed significantly for the better, indicating no improvement in parasympathetic function Patient subgroup with a significant decrease in A1c had a significant reduction of left ventricular mass (LVM) on echocardiogram.^Citation22 Patients without a significant improvement in A1c did not have a significant lowering of LVM There was a significant statistical relationship between coefficient of variation of the RR interval (CVNN) and LVM^Citation26 B. Subjective response to questionnaire^Citation27 Peripheral nerves Feet (numbness, tingling, burning, and other pain) Eye (visual blurring) Genital (sexual function) Autonomic nervous system Gastrointestinal (diarrhea) Postural hypotension (imbalance) Positive responses in questions relating to nerve function correlated highly with positive responses in preservation of Ccreat

Table 6 Treatment of angiotensin signaling in microangiopathic remodeling

	Inflammation	Hemostasis	Oxidative stress	Vasodilation	Angiogenesis	Fibrosis
A. Endothelial function
1. Human study
a. Losartan: Flammer et al^Citation44		+	+	+
Type 2 diabetes
b. Losartan: Kramer et al^Citation45		+
No diabetes
c. EXP3179: Fortuno et al^Citation46			+
No diabetes
2. Animal study
a. EXP3179: Watanabe et al^Citation63				+	+
No diabetes
b. Valsartan: Michel et al^Citation64					+
Spironolactone					+
No diabetes
B. Retinal function
1. Animal study
a. Candesartan: Kim et al^Citation60			+		+
b. Fosinopril: Zheng et al^Citation58					+
c. Enalapril: Kim et al^Citation57					+
d. Candesartan: Fukumoto et al^Citation59	+		+		+
e. Valsartan: Wilkinson-Berka et al^Citation61					+
Spironolactone	+				+
C. Renal function
1. Human study
a. Irbesartan: Persson et al^Citation10	+
b. Protein kinase C inhibitors: Gruden et al^Citation56					+
Tyrosine kinase inhibitors
Human mesangial cells: no diabetes
c. Enalapril, losartan, and spironolactone: Furumatsu et al^Citation11						+
Nondiabetic
2. Animal study
a. ACE2: Qudit et al^Citation47	+		+			+
Akita diabetic mouse
b. Quinapril: Blanco et al^Citation83	+					+
Zucker obese rat
D. Cardiac function
1. Animal study
a. Enalapril: Ma et al^Citation49	+	+
Losartan	+	+
Sprague–Dawley rat
b. Trandolapril: Onozato et al^Citation50			+			+
Eplerenone			+			+
Dahl salt-sensitive rat
c. Quinapril: Nemeth et al^Citation51						+
Spironolactone						+

Note: + indicates a favorable response in returning marker toward control level.

Table 7 Studies that specifically mention that blood pressure was not changed or in which there was no difference between study groups when anti-angiotensin treatments reversed mechanisms of diabetic microvascular complications

A. Alloxan diabetic dog Avendano et al:^Citation55 both aminoguanidine and enalapril prevented ventricular stiffness associated with pathologic glycation of collagen over 6 months. There were no significant differences in aortic pressure, ejection fraction, or heart rate compared with controls despite the increased pressure/volume relationship. The concentration of ventricular collagen increased in the alloxan diabetic animals whether they were treated with enalapril or aminoguanidine or not treated B. Akita diabetic mouse Qudit et al:^Citation47 human recombinant angiotensin-converting enzyme 2 (ACE2), carboxypeptidase that transforms AT2 into A 1–7 without changing the ‘slightly elevated’ blood pressure of this animal, which has high blood glucose Factors that did change after 4 weeks of treatment included improvement in increased Protein kinase C Nitric oxide synthase oxidase NADPH oxidase Albuminuria Thickening of glomerular basement membrane Enlargement of glomerular mesangium Genes for collagen and actin C. Zucker obese rat Blanco et al^Citation83 Quinapril Endpoint Proteinuria Glomerular histology (nephrosclerosis) Interstitial histology (infiltrate)

Table 8 Nephrin functions in several tissues (kidney, pancreas, and possibly central nervous system)

Podocyte of kidney	Pancreas β-cells
Anchors adjacent foot processes by extracellular domain through attachment to actin cytoskeleton by its intracellular domain^Citation68	Anchors intracellular filaments of actin cytoskeleton^Citation66,Citation67
Requires assistance of other proteins (NCK, podocin, and syn protein family). Receptor for advanced glycated end products colocated with synaptopodin^Citation72	Requires assistance of syntaxin^Citation71 intracellularly in a way more closely cooperative than the functions of podocin and synaptopodin, where the leverage effect occurs extracellularly
Cooperates in translocation of glucose transporter protein vesicles across cytoplasm to dock at plasma membrane.^Citation69 Accompanied by VAMP, a protein that moves with other proteins that have taken the form of vesicles (granules). Process is critical for intake of fuel; insulin and adiponectin have a signaling role	Promotes translocation of insulin vesicles across cytoplasmic ‘cell web’ to dock at plasma membrane. Accompanied by VAMP. Process critical for timely insulin secretion^Citation70
Inhibits nuclear factor-κβ (NF-κβ).^Citation82 Animal model of mutant nephrin^Citation79,Citation80 adiponectin knockout^Citation81 have elevated NF-κβ, proteinuria, glomerular pathology corrected with replacement of nephrin	AGEs cause apoptosis. AGEs also can cross-link actin filament to alter the timing and amplitude of insulin secretion^Citation73
Coexpressed with myocardin, a protein of both cardiac and smooth muscle origin. Other podocyte proteins (smoothelin and calponin) relate strictly to a smooth muscle origin. Through smoothelin, podocyte responds to angiotensin 2 by contraction in actin-dependent manner.^Citation74 Podocytes have similarities to pericytes of the central nervous system and retina	Angiotensin 2 provokes apoptosis through NADPH oxidase; prevented by telmisartan^Citation75

Table 9 Pulsatile insulin secretion

A. Insulin secretion Insulin is secreted ∼10 times/h^Citation85 Hormones secreted in oscillations are more efficient than when equimolar amounts are tested by continuous infusion^Citation91^–^Citation93 B. Islets of Langerhans Glucagon and somatostatin secreted together at the same pace^Citation93 Insulin has a different cadence C. Type 2 diabetes Rhythm of insulin secretion disordered Amplitude increased at first, then after several years begins to decrease due to AT2 generated in islets^Citation94 D. Drugs that increase amplitude, but do not change rate of oscillations Sulfonylurea^Citation86 Glucagon-like peptide^Citation87 Sodium salicylate^Citation88 E. Drugs that decrease amplitude, but do not change secretion rate Thiazide diuretic^Citation88 α-Adrenergic agonist^Citation89,Citation90

AokiTTBenbarkaMMOkimuraMCLong-term intermittent intravenous insulin therapy and type 1 diabetes mellitusLancet199334288705155188102666

 PubMed Web of Science ®Google Scholar

AokiTTGrecuEOArcangeliMAChronic intermittent intravenous insulin therapy corrects orthostatic hypotension of diabetesAm J Med19959966836847503093

 PubMed Web of Science ®Google Scholar

AokiTTGrecuEOPrendergastJJArcangeliMAMeisenheimerREffect of chronic intermittent intravenous insulin therapy on antihypertensive medication requirements in IDDM subjects with hypertension and nephropathyDiabetes Care1995189126012658612440

 PubMed Web of Science ®Google Scholar

PerssonFRossingPHovindPIrbesartan treatment reduces biomarkers of inflammatory activity in patients with type 2 diabetes and microalbuminuria: an IRMA 2 substudyDiabetes200655123550355517130503

 PubMed Web of Science ®Google Scholar

FlammerAJHermannFWiesliPEffect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertensionJ Hypertens200725478579117351370

 PubMed Web of Science ®Google Scholar

KramerCSunkomatJWitteJAngiotensin II receptor-independent anti-inflammatory and antiaggregatory properties of losartan: role of active metabolite EXP3179Circ Res200290777077611964369

 PubMed Web of Science ®Google Scholar

FortunoABidegainJRobadorPLosartan metabolite EXP3179 blocks NADPH oxidase-mediated superoxide production by inhibiting protein kinase C: potential clinical implications in hypertensionHypertension200954474475019687351

 PubMed Web of Science ®Google Scholar

FurumatsuYNagasawaYTomidaKEffect of renin-angiotensin-aldosterone system triple blockade on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blockerHypertens Res2008311596718360019

 PubMed Web of Science ®Google Scholar

MehdiUFAdams-HuetBRaskinPVegaGLTotoRDAddition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathyJ Am Soc Nephrol200920122641265019926893

 PubMed Web of Science ®Google Scholar

DaileyGEBodenGHCreechRHJohnsonDGleasonREKennedyFPWeinrauchLAWeirMD’EliaJEffects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathyMetabolism200049111491149511092517

 PubMed Web of Science ®Google Scholar

BurgerAJWeinrauchLAD’EliaJAAronsonDEffect of glycemic control on heart rate variability in type I diabetic patients with cardiac autonomic neuropathyAm J Cardiol199984668769110498140

 PubMed Web of Science ®Google Scholar

AepfelbacherFCYeonSBWeinrauchLAD’EliaJBurgerAJImproved glycemic control induces regression of left ventricular mass in patients with type 1 diabetes mellitusInt J Cardiol2004941475114996474

 PubMed Web of Science ®Google Scholar

WeinrauchLABurgerAGleasonRELeeATD’EliaJALeft ventricular mass reduction in type 1 diabetic patients with nephropathyJ Clin Hypertens (Greenwich)20057315916415785157

 PubMedGoogle Scholar

WeinrauchLABaylissGGleasonRELeeATD’EliaJAUtilization of an abbreviated diabetes impact management scale to assess change in subjective disability during a trial of pulsatile insulin delivery demonstrates benefitMetabolism200958448849119303968

 PubMed Web of Science ®Google Scholar

WatanabeTSuzukiJYamawakiHSharmaVKSheuSSBerkBCLosartan metabolite EXP3179 activates Akt and endothelial nitric oxide synthase via vascular endothelial growth factor receptor-2 in endothelial cells: angiotensin II type 1 receptor-independent effects of EXP3179Circulation2005112121798180516172287

 PubMed Web of Science ®Google Scholar

MichelFAmbroisineMLDuriezMDelcayreCLevyBSilvestreJSAldosterone enhances ischemia-induced neovascularization through angiotensin II-dependent pathwayCirculation2004109161933193715078792

 PubMed Web of Science ®Google Scholar

KimJHKimJHYuYSChoCSKimKWBlockade of angiotensin II attenuates VEGF-medicated blood-retinal barrier breakdown in diabetic retinopathyJ Cereb Blood Flow Metab200929362162819107135

 PubMed Web of Science ®Google Scholar

ZhengZChenHXuXLiCGuQEffects of angiotensin-converting enzyme inhibitors and beta adrenergic blockers on retinal vascular endothelial growth factor expression in rat diabetic retinopathyExp Eye Res200784474575217303121

 PubMed Web of Science ®Google Scholar

KimHWKimJLLeeHKHurDYYunIHKimSDEnalapril alters expression of key growth factors in experimental diabetic retinopathyCurr Eye Res2009341197698719958114

 PubMed Web of Science ®Google Scholar

FukumotoMTakaiSIshizakiEInvolvement of angiotensin II-dependent vascular endothelial growth factor gene expression via NADPH oxidase in the retina in a type 2 diabetic rat modelCurr Eye Res2008331088589118853323

 PubMed Web of Science ®Google Scholar

Wilkinson-BerkaJLTanGJaworskiKMillerAGIdentification of a retinal aldosterone system and the protective effects of mineralocorticoid receptor antagonism on retinal vascular pathologyCirc Res2009104112413319038868

 PubMed Web of Science ®Google Scholar

GrudenGThomasSBurtDMechanical stretch induces vascular permeability factor in human mesangial cells: mechanisms of signal transductionProc Natl Acad Sci U S A1997942212112121169342371

 PubMed Web of Science ®Google Scholar

QuditGYLiuGCZhongJHuman recombinant ACE2 reduces the progression of diabetic nephropathyDiabetes201059252953819934006

 PubMed Web of Science ®Google Scholar

BlancoSBonetJLopezDCasasIRomeroRACE inhibitors improve nephrin expression in Zucker rats with glomerulosclerosisKidney Int Suppl200593S10S1415613060

 PubMed Web of Science ®Google Scholar

MaLJNakamuraSAldigierJCRegression of glomerulosclerosis with high-dose angiotensin inhibition is linked to decreased plasminogen activator inhibitor-1J Am Soc Nephrol200516496697615728787

 PubMed Web of Science ®Google Scholar

OnozatoMLTojoAKobayashiNGotoAMatsuokaHFujitaTDual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidneyNephrol Dial Transplant20072251314132217324946

 PubMed Web of Science ®Google Scholar

NemethZKokenyGGodoMIncreased renoprotection with ACE inhibitor plus aldosterone antagonist as compared to montherapies – the effect on podocytesNephrol Dial Transplant200924123640365119666910

 PubMed Web of Science ®Google Scholar

AvendanoGFAgarwalRKBasheyRIEffects of glucose intolerance on myocardial function and collagen-linked glycationDiabetes19994871443144710389851

 PubMed Web of Science ®Google Scholar

VermaRKovariISoofiANihalaniDPatrieKHolzmanLBNephrin ectodomain engagement results in SRC kinase activation, nephrin phosphorylation, NCK recruitment, and actin polymerizationJ Clin Invest200611651346135916543952

 PubMed Web of Science ®Google Scholar

LacyPEHowellSLYoungDAFinkCJNew hypothesis of insulin secretionNature19682195159117711794877537

 PubMed Web of Science ®Google Scholar

OrciLGabbayKMalaisseWJPancreatic beta-cell web: it’s possible role in insulin secretionScience197217526112811304551150

 PubMed Web of Science ®Google Scholar

WendtTTanjiNGuoJGlucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathyJ Am Soc Nephrol20031451383139512707408

 PubMed Web of Science ®Google Scholar

JewellJLLuoWOhEWangZThurmondDCFilamentous actin regulates insulin exocytosis through direct interaction with syntaxin 4J Biol Chem200828316107161072618285343

 PubMed Web of Science ®Google Scholar

CowardRJWelshGIKoziellANephrin is critical for the action of insulin on human glomerular podocytesDiabetes20075641127113517395751

 PubMed Web of Science ®Google Scholar

FornoniAJeonJVarona SantosJNephrin is expressed on the surface of insulin vesicles and facilitates glucose-stimulated insulin releaseDiabetes201059119019919833886

 PubMed Web of Science ®Google Scholar

OuchiNKiharaSAritaYAdiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathwayCirculation2000102111296130110982546

 PubMed Web of Science ®Google Scholar

HussainSRomioLSaleemMNephrin deficiency activates NF-kappaB and promotes glomerular injuryJ Am Soc Nephrol20092081733174319497968

 PubMed Web of Science ®Google Scholar

SheerinNSA novel role for nephrin in the maintenance of glomerular structureJ Am Soc Nephrol20092081661166319590059

 PubMed Web of Science ®Google Scholar

SharmaKRamachandra RaoSQuiGAdiponectin regulates albuminuria and podocyte function in miceJ Clin Invest200811851645165618431508

 PubMed Web of Science ®Google Scholar

ChuangPYYuQFangWUribarriJHeJCAdvanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factorKidney Int200772896597617667983

 PubMed Web of Science ®Google Scholar

SaleemSZavadilJBaillyMThe molecular and functional phenotype of glomerular podocytes reveals key features of contractile smooth muscle cellsAm J Physiol Renal Physiol20082954F959F97018684887

 PubMed Web of Science ®Google Scholar

SaitohYHongweiWUenoHMizutaMNakazatoMTelmisartan attenuates fatty-acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic beta-cellsDiabetes Metab200935539239719713141

 PubMed Web of Science ®Google Scholar

PorksenNMunnSSteersJVeldhuisJButlerPCEffects of glucose ingestion versus infusion on pulsatile insulin secretion: the incretin effect is achieved by amplification of insulin secretory burst massDiabetes19964510131713238826965

 PubMed Web of Science ®Google Scholar

WeigleDSKoerkerDJGoodnerCJPulsatile glucagon delivery enhances glucose production by perifused rat hepatocytesAm J Physiol19842474 Pt 1E564E5686496673

 PubMed Web of Science ®Google Scholar

JaspanJBLeverEPolonskyKSvan CauterEIn vivo pulsatility of pancreatic islet peptidesAm J Physiol19862512 Pt 1E215E2262874743

 PubMed Web of Science ®Google Scholar

LauTCarlssonPOLeungPSEvidence for a local angiotensingenerating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic isletsDiabetologia200447224024814722647

 PubMed Web of Science ®Google Scholar

JuhlCBPorksenNPincusSMHansenAPVeldhuisJDSchmitzOAcute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetesDiabetes20015081778178411473038

 PubMed Web of Science ®Google Scholar

RitzelRSchulteMPorksenNGlucagon-like peptide 1 increases secretory burst mass of pulsatile insulin secretion in patients with type 2 diabetes and impaired glucose toleranceDiabetes200150477678411289042

 PubMed Web of Science ®Google Scholar

MatthewsDRLangDABurnettMATurnerRCControl of pulsatile insulin secretion in manDiabetologia19832442312376345247

 PubMed Web of Science ®Google Scholar

RosengrenAHJokubkaRTojjarDOverexpression of alpha 2 A-adrenergic receptors contributes to type 2 diabetesScience2010327596221722019965390

 PubMed Web of Science ®Google Scholar

GribbleFMAlpha 2 A-adrenergic receptors and type 2 diabetesN Engl J Med2010362436136220107223

 PubMed Web of Science ®Google Scholar