Novel Approaches to Treatment and Prevention of Diabetic Nephropathy

A number of reports have documented favorable results of C-peptide supplementation in diabetics and animal models of insulinopenic diabetes. Nevertheless, additionally it is proven that good glycemic control is vital to reduce the potential risk of diabetes-induced complications. This project report looks into probable mechanisms for the favorable impact of C-peptide on glomerular hyperfiltration, plus a novel, painless route of insulin administration. The outcomes reveal that both C-peptide and its C-terminal penta-peptide sequence limit the diabetes-induced glomerular hyperfiltration within an hour. The outcomes furthermore show that C-peptide possibly minimizes diabetes-induced hyperfiltration via 3 different mechanisms: 1. Constriction of the afferent arteriole was exhibited on isolated vessels from diabetic mice. 2. A net dilation of the efferent arteriole was evident in vivo. 3. Inhibition of the Na+/K+-ATPase was revealed in vivo in diabetic rats along with vitro on isolated proximal tubular cells from diabetic rats. All of these mechanisms are well-known regulators of the net glomerular filtration pressure. The final section of this dissertation shows that intradermal administration with a newly developed patch-like microneedle device leads to similar insulin concentration compared to standard subcutaneous delivery….

Contents: Treatment and Prevention of Diabetic Nephropathy

Diabetes mellitus
Renal anatomy and physiology
Development of diabetic nephropathy
Alterations in glomerular filtration rate
Prevention and treatment of diabetic nephropathy
Prevention by proinsulin C-peptide
Mechanisms for C-peptide in diabetic nephropathy
Reducing diabetic glomerular hyperfiltration
The importance of glycemic control
Intradermal delivery of insulin
Aims of the investigation
Animals and induction of diabetes
Rats (Studies I, III, and IV)
Mice (Study II)
Experimental protocols, treatment regimens, drugs and preparation
Preparations and measurements
Anesthesia (Study I, III, and IV) and euthanasia
Surgical procedure (Study I, III and IV)
Blood pressure (Studies I, III and IV)
Tissue isolation, dissection and perfusion (Study II)
Measurements of oxygen consumption (Study III)
Blood flow estimations (Study III)
Measurements of tubular pressures (Study III)
Intradermal infusion of insulin (Study IV)
Analyses and calculations
Estimation of glomerular filtration rate (Study I and III)
Electrolyte analysis (Study I and III)
Measurements of arteriole contraction (Study II)
Calculations in Study III
Insulin analysis (Study IV)
Statistical method and presentation of data
Study I
Glomerular filtration rate
Blood glucose concentrations
Urinary sodium excretion
Study II
Afferent arteriole diameter
Rho-kinase inhibitor Y-27632
Study III
Blood pressure and renal parameters
Fractional Na+excretion and transported Na+
In vivo oxygen consumption
Micropuncture parameters: filtration pressures
In vitro oxygen consumption
Study IV
Plasma insulin concentrations
Blood glucose concentrations
Penta-peptide effects
C-peptide and glomerular hyperfiltration
Glomerular filtration rate and tubuloglomerular feedback
The tubular hypothesis of glomerular filtration
Separate effects on capillary and proximal pressure
Renal glomerular arteriolar vascular tone and blood flow
Cellular C-peptide signaling
C-peptide and Rho-kinase
C-peptide and oxygen consumption
Potential tissue or state-specificity of C-peptide
Lack of effect on normoglycemic animals…

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