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INTRODUCTION

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Diabetes mellitus is a spectrum of metabolic disorders arising from myriad pathogenic mechanisms, all resulting in hyperglycemia. Both genetic and environmental factors contribute to its pathogenesis, which involves insufficient insulin secretion, reduced responsiveness to endogenous or exogenous insulin, increased glucose production, or abnormalities in fat and protein metabolism. The resulting hyperglycemia may lead to both acute symptoms and metabolic abnormalities. Major sources of the morbidity of diabetes are the chronic complications that arise from prolonged hyperglycemia, including retinopathy, neuropathy, nephropathy, and cardiovascular disease. These chronic complications can be mitigated in many patients by sustained control of the blood glucose and treatment of comorbidities such as hypertension and dyslipidemia (Nathan, 2014; Orchard et al., 2015). There are now a wide variety of treatment options for hyperglycemia that target different processes involved in glucose regulation or dysregulation (Nathan, 2015).

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ABBREVIATIONS

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Abbreviations

AC: adenylyl cyclase

A1c: hemoglobin A1c

ADA: American Diabetes Association

BP: blood pressure

CHF: congestive heart failure

CNS: central nervous system

CSII: continuous subcutaneous insulin infusion

CV: cardiovascular

CVD: cardiovascular disease

DPP-4: dipeptidyl peptidase IV

EPI: epinephrine

GDM: gestational diabetes mellitus

GEF: guanine nucleotide exchange factor

GFR: glomerular filtration rate

GIP: glucose-dependent insulinotropic polypeptide

GIRK: G protein–coupled inwardly rectifying K+ channel

GK: glucokinase (hexokinase IV)

GLP: glucagon-like peptide

GLP-1RA: GLP-1 receptor agonist

GLUT: glucose transporter

G6P: glucose-6-phosphate

GPCR: G protein–coupled receptor

GRPP: glicentin-related pancreatic polypeptide

Hb: hemoglobin

HbA1c: hemoglobin A1c

HDL: high-density lipoprotein

HGP: hepatic glucose production

HNF: hepatocyte nuclear transcription factor

IAPP: islet amyloid polypeptide

ICU: intensive care unit

IFG: impaired fasting glucose

IFN: interferon

IGF-1: insulinlike growth factor 1

IGT: impaired glucose tolerance

IL: interleukin

IRS: insulin receptor substrate

Kir: inward rectifying K+ channel

LDL: low-density lipoprotein

MAOI: monoamine oxidase inhibitor

MODY: maturity onset diabetes of the young

mTOR: mammalian target of rapamycin

NE: norepinephrine

NPH: neutral protamine Hagedorn

NSAID: nonsteroidal anti-inflammatory drug

OCT: organic cation transporter

PC: prohormone convertase

PI3K: phosphatidylinositol-3-kinase

PIP3: phosphatidylinositol 3,4,5-trisphosphate

PLC: phospholipase

PPAR: peroxisome proliferator-activated receptor

SGLT2: sodium-glucose cotransporter 2

Shc: Src-homology-2-containing (protein)

SST: somatostatin

SUR: sulfonylurea receptor

TGF: transforming growth factor

TNF: tumor necrosis factor

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PHYSIOLOGY OF GLUCOSE HOMEOSTASIS

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Regulation of Blood Glucose

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The maintenance of glucose homeostasis, termed glucose tolerance, is a highly developed systemic process involving the integration of several major organs (Figure 47–1). Although the actions of insulin are of central importance, webs of interorgan communication via other hormones, nerves, local factors, and substrates also play vital roles. The pancreatic β cell is central in this homeostatic process, adjusting the amount of insulin secreted very precisely to promote glucose uptake after meals and to regulate glucose output from the liver during fasting.

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Figure 47–1

Insulin, glucagon, and glucose homeostasis. A. Fasting State–In healthy humans, plasma glucose is maintained in a range from 4.4 to 5 ...

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