Many factors increase the risk of developing T2DM, including family history, age, obesity, and lack of physical activity. Also, DM occurs more frequently in women with prior gestational DM and in individuals with hypertension or dyslipidemia. Symptoms of marked hyperglycemia include polyuria, polydypsia, weight loss, polyphagia, and blurred vision. Although the degree of hyperglycemia seen with T2DM may not cause symptoms initially, it is sufficient to cause pathologic and functional changes in target tissues, and as such, will increase the risk of microvascular and macrovascular complications.
These long-term complications include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Diabetic patients also have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease.
A summary of the major factors responsible for maintenance of normal glucose tolerance in healthy subjects is provided in the Table. The primary tissues involved in glucose utilization include the brain, muscle, fat, and the splanchnic area, with muscle tissue comprising the most important site of peripheral glucose uptake. Knowledge of the fundamentals of normal glucose homeostasis is essential to understanding the pathophysiologic derangements that may result from glucose imbalance disorders.
Conditions such as T2DM are characterized by an imbalance in glucose regulation, causing chronic hyperglycemia and ultimately leading to multiorgan damage. Several factors are implicated in the development of T2DM, including insulin resistance, insulin deficiency, increased hepatic glucose production, and adipocyte dysfunction. An increasingly clear understanding of these derangements has helped both researchers and clinicians to better manage T2DM and improve clinical outcomes.
Author disclosure: Dr Triplitt reports being a consultant or a member of the advisory board for Roche and Takeda Pharmaceuticals.
Authorship information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Address correspondence to: E-mail: Curtis. Triplitt uhs-sa. Institute for Value-Based Medicine. About AJMC. Examining the Mechanisms of Glucose Regulation.
March 28, Curtis L. Normal Glucose Homeostasis Glucose, a fundamental source of cellular energy, is released by the breakdown of endogenous glycogen stores that are primarily located in the liver. National Diabetes Fact Sheet , Center for Disease Control and Prevention. Accessed August 21, American Diabetes Association. Economic costs of diabetes in the U.
For people with type 2 diabetes, a progressive decrease in the concentration of insulin in the blood develops. Not only do the beta cells release less insulin as type 2 diabetes progresses, they also release it slowly and in a different pattern than that of healthy people Monnier et al.
Without sufficient insulin, the glucose-absorbing tissues—mainly skeletal muscle, liver, and adipose tissue—do not efficiently clear excess glucose from the bloodstream, and the person suffers the damaging effects of toxic chronic hyperglycemia. At first, the beta cells manage to manufacture and release sufficient insulin to compensate for the higher demands caused by insulin resistance.
Eventually, however, the defective beta cells decrease their insulin production and can no longer meet the increased demand. At this point, the person has persistent hyperglycemia. A downward spiral follows. The hyperglycemia and hyperinsulinemia caused by the over-stressed beta cells create their own failure. In type 2 diabetes, the continual loss of functioning beta cells shows up as a progressive hyperglycemia.
How would you explain insulin resistance differently to someone with type 1 diabetes and someone with type 2 diabetes? Together, insulin resistance and decreased insulin secretion lead to hyperglycemia, which causes most of the health problems in diabetes.
The acute health problems—diabetic ketoacidosis and hyperosmolar hyperglycemic state—are metabolic disorders that are directly caused by an overload of glucose. In comparison, the chronic health problems—eye, heart, kidney, nerve, and wound problems—are tissue injury, a slow and progressive cellular damage caused by feeding tissues too much glucose ADA, Hyperglycemic damage to tissues is the result of glucose toxicity. There are at least three distinct routes by which excess glucose injures tissues:.
If you are attending a virtual event or viewing video content, you must meet the minimum participation requirement to proceed. If you think this message was received in error, please contact an administrator. Return to Course Home. Fuels of the Body To appreciate the pathology of diabetes, it is important to understand how the body normally uses food for energy. Hormones of the Pancreas Regulation of blood glucose is largely done through the endocrine hormones of the pancreas, a beautiful balance of hormones achieved through a negative feedback loop.
The glucose becomes syrupy in the bloodstream, intoxicating cells and competing with life-giving oxygen. Optimal health requires that: When blood glucose concentrations are low, the liver is signaled to add glucose to the circulation. When blood glucose concentrations are high, the liver and the skeletal muscles are signaled to remove glucose from the circulation. Test Your Knowledge Glycogen is: A hormone produced in the pancreas. A polysaccharide that is stored in the liver.
Produced in the striated muscles when exercising. An energy reserve that is slow to mobilize in an emergency. Apply Your Knowledge If you want to lose weight, what fuel would you decrease in your diet and what fuels would you increase? Is a hormone that acts on the liver to convert excess glucose into glycogen. Inhibits the uptake and use of glucose by skeletal muscles.
Is manufactured and secreted by the alpha cells of the pancreas. Apply Your Knowledge How would you explain the function of insulin to your patient with diabetes? Test Your Knowledge Glucagon: Is a peptide hormone that is stored in the pancreas.
Is used to treat hyperglycemia by increasing the uptake of glucose in muscles. Is a hormone that acts on the liver to convert glycogen back into glucose. Stimulates the production of insulin. Apply Your Knowledge How is glucagon available by injection? Test Your Knowledge People with type 2 diabetes have: Insulin sensitivity, which is an over-reaction of cells to insulin. No beta cells in their pancreas and no circulating insulin at all. Chronic hypoglycemia.
Insulin resistance, which is a decreased response of cells to insulin. Apply Your Knowledge How would you explain to your patient what lifestyle behaviors create insulin resistance? Cell 3 — Cell Metab 13 2 — Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 6 — POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels.
Elife — Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med 16 4 —5. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci — Boyden ES. A history of optogenetics: The development of tools for controlling brain circuits with light. F Biol Rep 3 1 :1— A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia.
Cell Metab 20 6 —7. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 1 — Arterial baroreceptors sense blood pressure through decorated aortic claws. Cell Rep 29 8 — Vagal sensory neuron subtypes that differentially control breathing.
Genetic identification of vagal afferents that control hunger. Cell — A neural circuit for gut-induced reward. An anterograde tracing study of the vagal innervation of rat liver, portal vein and biliary system. Anat Embryol Berl 5 — Neuhuber WL. Vagal afferent fibers almost exclusively innervate islets in the rat pancreas as demonstrated by anterograde tracing. J Auton Nerv Syst 29 1 —8. Hypothalamic detection of macronutrients via multiple gut-brain pathways.
Cell Metab — J Neurophysiol 99 4 — Mol Metab 3 9 — Genetic variance contributes to ingestive processes: A survey of 2-deoxy-D-glucose-induced feeding in eleven inbred mouse strains. Physiol Behav 87 3 — Glucose metabolism in vivo in four commonly used inbred mouse strains.
Diabetes 57 7 —9. Diabetes 55 7 —6. Metabolic pitfalls of CNS cre-based technology. Cell Metab 18 1 —8. Roth BL. Neuron 89 4 — Science —7. Hyperinsulinemic-euglycemic clamp in the conscious rat. J Vis Exp 7 48 Hyperinsulinemic-euglycemic clamps in conscious, unrestrained mice. J Vis Exp Fully implantable arterial blood glucose device for metabolic research applications in rats for two months.
J Diabetes Sci Technol Chaudhary P, Schreihofer AM. Improved glucose homeostasis in male obese zucker rats coincides with enhanced baroreflexes and activation of the nucleus tractus solitarius.
Sanders NM, Ritter S. Repeated 2-deoxy-D-glucose-induced glucoprivation attenuates Fos expression and glucoregulatory responses during subsequent glucoprivation. Diabetes Recurrent hypoglycemia is associated with loss of activation in rat brain cingulate cortex.
Endocrinology Feeding and neuroendocrine responses after recurrent insulin-induced hypoglycemia. Physiol Behav Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats. Metabolism Repetitive hypoglycemia reduces activation of glucose-responsive neurons in C1 and C3 medullary brain regions to subsequent hypoglycemia.
Am J Physiol - Endocrinol Metab Effect of acute and antecedent hypoglycemia on sympathetic neural activity and catecholamine responsiveness in normal rats. Recurrent insulin-induced hypoglycemia causes site-specific patterns of habituation or amplification of CNS neuronal genomic activation.
Neuroscience Diabetes impairs hypothalamo-pituitary-adrenal HPA responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses. Orexin signaling is necessary for hypoglycemia-induced prevention of conditioned place preference.
Trends Endocrinol Metab 31 9 — Glucoreceptors controlling feeding and blood glucose: location in the hindbrain. Science —2. The forebrain is not essential for sympathoadrenal hyperglycemic response to glucoprivation. Science —4. Hindbrain catecholamine neurons control multiple glucoregulatory responses. Physiol Behav 89 4 — Antecedent hindbrain glucoprivation does not impair the counterregulatory response to hypoglycemia. Diabetes 56 1 — Localization of glucokinase gene expression in the rat brain.
Diabetes 49 5 — NTS catecholamine neurons mediate hypoglycemic hunger via medial hypothalamic feeding pathways. Diabetes 54 11 — Key Role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57 2 — Recombinase-driver rat lines: Tools, techniques, and optogenetic application to dopamine-mediated reinforcement.
Neuron 72 5 — A Phox2b bac transgenic rat line useful for understanding respiratory rhythm generator neural circuitry.
PLoS One 10 7 :1— Selective pharmacogenetic activation of catecholamine subgroups in the ventrolateral medulla elicits key glucoregulatory responses.
Endocrinology 1 — Repeated pharmacogenetic catecholamine neuron activation in the ventrolateral medulla attenuates subsequent glucoregulatory responses. Diabetes 69 12 — Neuron 95 1 — Little fish, big data: Zebrafish as a model for cardiovascular and metabolic disease.
Physiol Rev 97 3 — The emerging use of zebrafish to model metabolic disease. Blood sugar measurement in zebrafish reveals dynamics of glucose homeostasis.
Zebrafish 7 2 — Dynamic glucoregulation and mammalian-like responses to metabolic and developmental disruption in zebrafish. Gen Comp Endocrinol 2 — Sci Rep 7 1 :1— Cruz-Garcia L, Schlegel A. Lxr-driven enterocyte lipid droplet formation delays transport of ingested lipids. J Lipid Res 55 9 — Visualizing digestive organ morphology and function using differential fatty acid metabolism in live zebrafish. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus.
J Clin Endocrinol Metab ; 84 : — Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes. Diabetes ; 48 : — Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Insulin regulates leptin secretion from 3T3-L1 adipocytes by a PI 3 kinase independent mechanism.
Exp Cell Res ; : — Insulin stimulates both leptin secretion and production by rat white adipose tissue. Insulin-regulated expression of adiponectin receptors in muscle and fat cells. Cell Biol Int ; 36 : — Regulation of adiponectin and leptin secretion and expression by insulin through a PI3K-PDE3B dependent mechanism in rat primary adipocytes. Biochem J ; : — Insulin regulates the expression of adiponectin and adiponectin receptors in porcine adipocytes.
Domest Anim Endocrinol ; 34 : — Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Adiponectin-induced ERK and Akt phosphorylation protects against pancreatic beta cell apoptosis and increases insulin gene expression and secretion.
Globular adiponectin augments insulin secretion from pancreatic islet beta cells at high glucose concentrations. Endocrine ; 30 : — Apelin, a newly identified adipokine up-regulated by insulin and obesity. Regul Pept ; : 27— Chemerin regulates beta-cell function in mice.
Sci Rep ; 1 : Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes. FEBS Lett ; : — Chemerin is a novel adipocyte-derived factor inducing insulin resistance in primary human skeletal muscle cells. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose.
Diabetes ; 57 : — Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action.
Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes. The release of the adipocytokine visfatin is regulated by glucose and insulin.
Visfatin regulates insulin secretion, insulin receptor signalling and mRNA expression of diabetes-related genes in mouse pancreatic beta-cells. J Mol Endocrinol ; 44 : — Adipokines and insulin resistance.
Mol Med ; 14 : — FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling.
Fibroblast growth factor is induced in human skeletal muscles by hyperinsulinemia. FGF21 is an Akt-regulated myokine. Arch Physiol Biochem ; : 47— Interleukin-6 regulates pancreatic alpha-cell mass expansion.
Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.
Nat Med ; 17 : — A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Mortality results. Diabetes ; 19 Suppl : — The UGDP controversy: thirty-four years of contentious ambiguity laid to rest. Perspect Biol Med ; 47 : — Functional coupling of Kir6. Association and stoichiometry of K ATP channel subunits. Neuron ; 18 : — J Mol Endocrinol ; 22 : — Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.
Neuron ; 16 : — A novel sulfonylurea receptor forms with BIR Kir6. Sulfonylurea stimulation of insulin secretion. Diabetes ; 51 Suppl 3 : S—S Characterization of low-affinity binding sites for glibenclamide on the Kir6. J Physiol ; Pt 1 : 35— Acute effect of glimepiride on insulin-stimulated glucose metabolism in glucose-tolerant insulin-resistant offspring of patients with type 2 diabetes. Diabetes Care ; 25 : — The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes.
Diabetes ; 31 4 Pt 1 : — The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes ; 33 : — ATP4- mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites.
A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care ; 30 : — Rates of hypoglycemia in users of sulfonylureas.
J Clin Epidemiol ; 50 : — Avoiding hypoglycemia: a key to success for glucose-lowering therapy in type 2 diabetes. Vasc Health Risk Manag ; 9 : — Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes ; 47 : — Tissue specificity of sulfonylureas: studies on cloned cardiac and beta-cell K ATP channels. Tissue selectivity of antidiabetic agent nateglinide: study on cardiovascular and beta-cell K ATP channels. J Pharmacol Exp Ther ; : — Pancreatic beta-cell K ATP channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide.
Stimulating activity of A on insulin release in in situ hamster pancreatic perfusion. Pharmacology ; 51 : — Hypoglycaemic and insulinotropic effects of a novel oral antidiabetic agent, - -N- transisopropylcyclohexanecarbonyl -D-phenylalanine A Br J Pharmacol ; : — Kinetics-effect relations of insulin-releasing drugs in patients with type 2 diabetes: brief overview.
Diabetes ; 53 Suppl 3 : S—S Repaglinide improves blood glucose control in sulphonylurea-naive type 2 diabetes. Diabetes Res Clin Pract ; 53 : — Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects.
Structurally modified analogues of glucagon-like peptide-1 GLP-1 and glucose-dependent insulinotropic polypeptide GIP as future antidiabetic agents.
Curr Pharm Des ; 10 : — N-terminal His 7 -modification of glucagon-like peptide-1 amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity. Biol Chem ; : — A novel, long-acting agonist of glucose-dependent insulinotropic polypeptide suitable for once-daily administration in type 2 diabetes. Biological activity of GLPanalogues with N-terminal modifications.
Regul Pept ; 79 : 93— Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab ; 8 : — Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study.
Clin Ther ; 30 : — Effects of exenatide exendin-4 on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.
Diabetes Care ; 28 : — Diabetes Care ; 33 : — Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a week randomised, parallel-group, multinational, open-label trial LEAD Lancet ; : 39— Diabetes Care ; 32 : — Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes GetGoal-Mono.
Diabetes Care ; 35 : — Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med ; 27 : — Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin GetGoal-S.
J Diabetes Complications ; 28 : — The insulinotropic actions of glucose-dependent insulinotropic polypeptide GIP and glucagon-like peptide-1 in normal and diabetic subjects. Regul Pept ; 51 : 63— Exogenous glucose-dependent insulinotropic polypeptide worsens post prandial hyperglycemia in type 2 diabetes.
GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes ; 60 : — Glucagon-like peptide-1 and glucose-dependent insulin-releasing polypeptide plasma levels in response to nutrients.
Digestion ; 56 : — Insulinotropic action of glucagonlike peptide-I- in diabetic and nondiabetic subjects. Diabetes Care ; 15 : — Mechanism by which metformin reduces glucose production in type 2 diabetes. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes.
Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes ; : 27— Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res ; 6 : 47— Glucose plus metformin compared with glucose alone on beta-cell function in mouse pancreatic islets.
Biomed Rep ; 3 : — Effects of rosiglitazone and metformin on pancreatic beta cell gene expression. Int J Biol Sci ; 10 : — Metformin-induced stimulation of AMP-activated protein kinase in beta-cells impairs their glucose responsiveness and can lead to apoptosis. Biochem Pharmacol ; 68 : — Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab ; 89 : — Lipotoxicity in human pancreatic islets and the protective effect of metformin.
Diabetes ; 51 Suppl 1 : S—S Troglitazone-induced fulminant hepatic failure. Acute Liver Failure Study Group. Dig Dis Sci ; 45 : — Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med ; : 38— Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration.
Am J Gastroenterol ; 95 : — Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.
N Engl J Med ; : — EMBO J ; 15 : — Role of PPAR- gamma agonist thiazolidinediones in treatment of pre-diabetic and diabetic individuals: a cardiovascular perspective. Effect of pioglitazone on body composition and energy expenditure: a randomized controlled trial. Metabolism ; 54 : 24— Metabolism ; 53 : — Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes.
Mol Cell Endocrinol ; : 78— Molecular mechanism by which pioglitazone preserves pancreatic beta-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARgamma agonist. Low-dose acarbose does not delay digestion of starch but reduces its bioavailability. Diabet Med ; 24 : — Improvement of metabolic control in insulin dependent diabetics treated with the alpha-glucosidase inhibitor acarbose for two months. Diabetologia ; 21 : — Acarbose in the treatment of elderly patients with type 2 diabetes.
Diabetes Res Clin Pract ; 59 : 37— Effect of acarbose on insulin sensitivity in elderly patients with diabetes. Diabetes Care ; 23 : — The effect of short-term alpha-glucosidase inhibition on carbohydrate and lipid metabolism in type II noninsulin-dependent diabetics. Metabolism ; 36 : — The effects of the alpha-glucosidase inhibitor BAY g Acarbose on postprandial blood glucose, serum insulin, and triglyceride levels: dose-time-response relationships in man. Res Exp Med Berl ; : 87— Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes.
Evaluation of effect of acarbose consumption on weight losing in non-diabetic overweight or obese patients in Kerman. J Res Med Sci ; 18 : — JAMA ; : — Effects of miglitol, an alpha-glucosidase inhibitor, on glycaemic status and histopathological changes in islets in non-obese, non-insulin-dependent diabetic Goto-Kakizaki rats. Br J Nutr ; 98 : — Inhibition of progressive reduction of islet beta-cell mass in spontaneously diabetic Goto-Kakizaki rats by alpha-glucosidase inhibitor. Metabolism ; 49 : — The alpha-glucosidase inhibitor miglitol delays the development of diabetes and dysfunctional insulin secretion in pancreatic beta-cells in OLETF rats.
Eur J Pharmacol ; : 51—
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