II. Pathophysiology of Type 2 Diabetes Mellitus Flashcards
Type 2 diabetes mellitus is the predominant form of diabetes worldwide, accounting for __% of cases globally.
90-95%
TRUE or FALSE: The prevalence of obesity and T2DM in children has risen dramatically over the past decade.
TRUE
Epidemiologic determinants of and risk factors for type 2 diabetes mellitus – Genetic Factors (2)
Genetic markers
Family history
Epidemiologic determinants of and risk factors for type 2 diabetes mellitus – Demographic Characteristics (2)
Age
Ethnicity
Epidemiologic determinants of and risk factors for type 2 diabetes mellitus – Behavioral and Lifestyle-Related Risk Factors (7)
Obesity (including distribution of obesity and duration)
Physical inactivity
Diet
Stress
Westernization, urbanization, modernization
Medications
Shift work
Epidemiologic determinants of and risk factors for type 2 diabetes mellitus – Metabolic Determinants and Intermediate-Risk Categories of Type 2 Diabetes (6)
Impaired glucose tolerance
Insulin resistance
Gestational diabetes
Offspring of women with diabetes during pregnancy
Intrauterine malnutrition or overnutrition
Microbiome composition
3 cardinal abnormalities in persons with T2DM
1) Resistance to the action of insulin in peripheral tissues, particularly muscle, fat, and liver (the classical tissues of insulin action)
2) Defective insulin secretion, particularly in response to a glucose stimulus, although absolute levels may be high, low, or normal
3) Increased glucose production by the liver leading to hyperglycemia in the fasting state
Earliest detectable abnormality in those predisposed to T2DM
Insulin resistance
Most common factors that place an increased secretory burden on the beta cell (additional insulin resistance factors) (4)
Puberty, pregnancy, a sedentary lifestyle, and overeating leading to weight gain
TRUE or FALSE: No single genetic alternation has been identified as the driver of beta-cell failure.
TRUE
TRUE or FALSE: In the monogenic forms of diabetes, enviromental factors play a role in determining whether the person develops diabetes.
FALSE
In the monogenic forms of diabetes, the gene involved is both necessary and sufficient to cause diabetes. In other words, environmental factors play little or no role in determining whether a genetically predisposed person develops clinical diabetes, although there is some variation in penetrance of disease.
3 clinical syndromes caused by mutations in the insulin receptor gene
1) Type A insulin resistance - mutation in intracellular tyrosine kinase domain
2) Donohue syndrome - extracellular domain
3) Rabson-Mendenhall syndrome - extracellular domain
Some may remain normoglycemic due to massive elevators of endogenous insulin secretion, whereas others have presented with hyperglycemia that fails to respond to insulin therapy
3 features of Type A insulin resistance
Insulin resistance, acanthosis nigricans (often in the absence of obesity), and hyperandrogenism (most often in adolescents or young adults)
Features of Donohue syndrome (formerly called leprechaunism)
Severe intrauterine growth retardation, abnormal facies leading to the name of the syndrome, and death within the first 1 to 2 years of life (may have episodes of hypoglycemia despite insulin resistance)
Features of Rabson-Mendenhall syndrome
Short stature, protuberant abdomen, and abnormalities of teeth and nails; pineal hyperplasia was a characteristic in the original description of this syndrome
Features of lipodystrophic diabetes
Can either be genetic or acquired, and partial or generalized
Syndromes of severe insulin resistance associated with lipoatrophy (loss of fat) and lipodystrophy (loss and maldistribution of fat)
3 Characteristics of lipodystrophic diabetes
Paucity of fat, insulin resistance, and hypertriglyceridemia
Treatment for generalized lipodystrophies
Leptin-replacement therapy (improves glycemic control, decreases fatty liver disease, and decreases circulating triglyceride levels)
Features of generalized lipodystrophies
Persons with generalized lipodystrophy are quite rare but easily diagnosed by the loss of subcutaneous fat throughout the entire body, with severe metabolic abnormalities, including severe fatty liver disease, sometimes leading to ascites and esophageal varices. This is associated with very low levels of adipose tissue-derived hormones leptin and adiponectin.
Features of partial lipodystrophies
Frequently missed, and phenotypes vary significantly by mutation and gender. Leptin levels may be in the normal range or slightly below the normal range but do not show the elevations generally seen with obesity. Diagnosis is made by clinical phenotype
What is the rare condition that may appear during childhood, adolescence, or young adulthood, characterized by fat loss affecting large areas of the body (initially usually the face, arms, and legs), and is thought to be an autoimmune disorder?
Acquired generalized lipodystrophy (also known as Seip-Lawrence syndrome)
First evidence of genetic association with T2DM (first polymorphism identified)
Gly972Arg in Insulin Receptor Substrate 1 (IRS1) Gene - results in impaired insulin-stimulated phosphatidylinositol 3-kinase signaling, but plays only a minor role in overall T2DM risk
Of the common variants that determine diabetes risk, variants at this locus have the greatest impact
Transcription Factor 7-Like 2 Gene (TCF7L2)
Mutations in this genes are the most common cause of neonatal diabetes
KATP Channel Genes: KCNJ11 and ABCC8
Generally treatable with sulfonylureas
Neonatal diabetes caused by these mutations are generally treatable with sulfonylureas rather than insulin
KATP Channel Genes: KCNJ11 and ABCC8
Beta-cell K ATP channel is composed of 2 subunits - Kir6.2 (KCNJ11), component of K channel, and SUR1 (ABCC8), sulfonylurea receptor.
Loss of function mutations in this gene cause familial partial lipodystrophy type 3 (FPLD3) and may show dramatic improvement when treated with the thiazolidinedione PPAR agonists.
Peroxisome Proliferator-Activated Receptor gamma gene (PPAR gamma)
First discovered MODY gene
HNF4 alpha (leads to abnormalities in insulin secretion)
Maternally imprinted transcription factor (effects only occur when the polymorphism is inherited from mother to daughter) that, when mutated, influences T2DM risk by causing a redistribution of fat from gynoid to visceral depots and increasing adipocyte size
Kruppel-like Factor 14 (KLF14)
TRUE or FALSE and FILL IN: The diabetes genes identified to date individually lead to a MODEST increase in the risk of diabetes. Persons with these individual polymorphisms have odds ratios between ___. The presence of multiple polymorphisms in a single individual substantially INCREASES the risk.
TRUE
1.10 and 1.45
TRUE or FALSE: Early Genome-Wide Association Studies suggested that a substantial proportion of the genetic variants associated with an increased risk for diabetes were in genes that might alter insulin sensitivity.
FALSE
Early Genome-Wide Association Studies suggested that a substantial proportion of the genetic variants associated with an increased risk for diabetes were in genes that might alter insulin secretion, but recent studies showed that the number of SNPs associated with decreased insulin sensitivity have increased.
TRUE or FALSE: The majority of the SNPs associated with risk of T2DM appear to reside in noncoding regions of the chromatin. Some exist in open chromatin regions alternatively called stretch enhancers.
TRUE
The total number of loci linked to T2DM is large but actually account for a small proportion (estimated at no more than 5-10% of total genetic risk), which means that there is still missing heritability.
What is the hypothesis that states that common diseases are due to multiple, but rare, variants with large effects?
Rare variant hypothesis
Epigenetic marks can influence the expression of genes and influence disease risk. Give 1 factor studied during the Dutch Hunger Winter during WWII.
Perinatal nutrition influence on risk for obesity in offspring (restricted to 400-800 calories per day)
The insulin receptor has how many alpha and beta subunits, and which one is responsible for insulin binding and which is catalytically active?
The insulin receptor consists of 2 insulin-binding alpha subunits and 2 catalytically active beta subunits, disulfide linked into an alpha2beta2 heterotetrameric complex.
What comprise the 3 critical nodes of insulin signaling that regulate a majority of the metabolic and transcriptional effects downstream of insulin activation?
- Insulin receptor substrates (IRS)
- Phosphoinositide 3-kinase (PI3K)
- Akt kinase (also known as protein kinase B)
Insulin stimulates glucose uptake by translocation of ___ from an intracellular pool to the surface of cells of the skeletal muscle and adipose tissue.
GLUT4
Effect of insulin on protein homeostasis
In muscle, insulin promotes hypertrophy by both enhancing protein synthesis and suppressing protein degradation pathways.
Effect of insulin on lipid storage
- Insulin stimulates rapid and potent increases in adipose tissue glucose uptake that is then converted into glycerol-3-phosphate, used to synthesize triglycerides from fatty acids.
- Fatty acid transport into adipose is also increased by insulin, which likely involves translocation of fatty acid transporters.
- Glucose also activates carbohydrate response element-binding proteins to upregulate glycolytic and lipogenic genes in adipocytes.
- Insulin also regulates fat distribution, as well as hepatic lipogenesis, the primary site of de novo lipogenesis in the body.
TRUE or FALSE: Patients with T2DM and metabolic syndrome have a paradoxical upregulation of hepatic lipogenesis and dyslipidemia.
TRUE (exact mechanisms have not been elucidated)
Regulators of hepatic glucose production
Insulin and glucagon (insulin being dominant over glucagon, both in regulation of gluconeogenesis and glycogenolysis)
Direct mechanism by which insulin decreases endogenous glucose production
In its direct action, portal insulin suppresses glucose production by inhibiting glycogenolysis and gluconeogenesis by insulin receptor activation.
Indirect or peripheral mechanisms by which insulin decreases endogenous glucose production (2)
- Insulin profoundly decreases glucagon secretion by the alpha cell of the pancreas through systemic and paracrine effects. The decrease in glucagon secretion decreases the activation of glycogenolysis and gluconeogenesis.
- Insulin decreases substrates for gluconeogenesis, such as alanine from muscle protein degradation, and glycerol and free fatty acid levels, by suppressing lipolysis in adipose tissue.
TRUE or FALSE: Clinically, hepatic insulin resistance plays an important role in the hyperglycemia of T2DM, and the impaired suppression of hepatic glucose output appears to be quantitatively similar to, or even larger than, the defect in stimulation of peripheral glucose disposal.
TRUE
TRUE or FALSE: Low plasma insulin levels impair insulin-mediated suppression of hepatic glucose output.
TRUE
Insulin-mediated suppression of hepatic glucose output is impaired at both low and high plasma insulin levels in T2DM.
TRUE or FALSE: Hepatic glucose production is elevated early in the course of diabetes.
TRUE (treat patients with metformin)
Effect of insulin and consequence of insulin resistance in Beta cells
Effect: Survival/proliferation and First-phase secretion
Consequence: Impairment of growth of beta cells and loss of first-phase insulin secretion
Effect of insulin and consequence of insulin resistance in Apha cells
Effect: Glucagon suppression
Consequence: Glucose intolerance, increased glucagon secretion, and progressive hyperinsulinemia
Effect of insulin and consequence of insulin resistance in Endothelium
Effect: Vasodilation (via nitric oxide production)
Consequence: 2-3 fold increase in atherosclerotic lesions in an atherogenic mouse model
Effect of insulin and consequence of insulin resistance in Cardiomyocyte
Effect: Glucose oxidation and Hypertrophy
Consequence: Fatty acid oxidation and Autophagy
Effect of insulin and consequence of insulin resistance in Macrophage
Effect: Cytokine release
Consequence: Endoplasmic reticulum stress, Apoptosis, and Plaque progression
Effect of insulin and consequence of insulin resistance in Brain/Neuron
Effect: Satiety, Mood stabilization, Cholesterol synthesis
Consequence: Associated with Alzheimer disease
TRUE or FALSE: Insulin action is required for glucose uptake in the brain.
FALSE
Insulin action is NOT required for glucose uptake in the brain because it predominantly expresses the insulin-independent glucose transporters GLUT1 and GLUT3.
Predominantly expressed isoform of insulin receptor in the brain
Isoform A (missing exon 11), which is in contrast to most other tissues in the body which predominantly express isoform B
Effect of insulin resistance on the 1) skeletal muscle, 2) adipocyte, and 3) liver
Insulin resistance is primarily manifested by decreased insulin-stimulated glucose transport and metabolism in skeletal muscle, impaired insulin suppression of adipocyte lipolysis, and impaired ability of insulin to suppress hepatic glucose output.
Gold standard for determining insulin sensitivity/resistance in an individual
Hyperinsulinemic euglycemic clamp (costly, invasive, and time consuming)
Other methods of determining insulin resistance aside from hyperinsulinemic euglycemic clamp
Steady-state plasma glucose method of Reaven
Bergman minimal model of glucose disposal
How is the Hyperinsulinemic euglycemic clamp performed
Constant infusion of insulin to produce hyperinsulinemia and second infusion containing glucose given concurrently and adjusted to produce euglycemia
Since the individual is in steady state, the glucose infusion rate represents the rate of glucose uptake/disposal into muscle, fat, and other tissues under hyperinsulinemic conditions (i.e., the insulin sensitivity of the patient)
What is the Disposition Index
Combined measure of insulin sensitivity and insulin secretion
Mathematical measures of insulin resistance
HOMA-IR (homeostatic model assessment of insulin resistance) - computed using fasting glucose and insulin levels
QUICKI (quantitative insulin-sensitivity check index) - based on reciprocal of the logarithm of HOMA-IR
TRUE or FALSE: Central (intraabdominal or visceral) adiposity is more strongly linked to insulin resistance and to several important metabolic variables, including elevated plasma glucose, insulin, total plasma cholesterol, and triglyceride concentrations, than is total adiposity.
TRUE
TRUE or FALSE: Abdominal fat is more lipolytically active than subcutaneous fat, perhaps because of its greater complement of adrenergic receptors, and is resistant to the antilipolytic effects of insulin. This leads to increased lipase activity and greater flux of fatty acids into the circulation, with the portal circulation receiving the greatest fatty acid load.
TRUE
TRUE or FALSE: Abdominal fat makes and releases more adiponectin, which is a beneficial adipokine, compared to total subcutaneous fat.
FALSE
Subcutaneous fat makes and releases more adiponectin, which is a beneficial adipokine.
TRUE or FALSE: Subcutaneous fat has higher levels of 11beta-hydroxysteroid dehydrogenase type 1 which enhances conversion of inactive cortisone to active cortisol, which might change adipocytes to increase lipolysis and alter the production of adipokines.
FALSE
The high levels of 11beta-hydroxysteroid dehydrogenase type 1 in intraabdominal fat could result in enhanced conversion of inactive cortisone to active cortisol, which might change adipocytes to increase lipolysis and alter the production of adipokines.
TRUE or FALSE: Low levels of insulin downregulates insulin receptors and sensitizes postreceptor pathways.
FALSE
Elevated concentrations of of insulin downregulates insulin receptors and desensitizes postreceptor pathways.
TRUE or FALSE: Chronic overnutrition can alter normal cellular signals, causing insulin resistance.
TRUE
Most excess nutritions, whether carbohydrate, protein, or lipid, are ultimately stored as triglyceride in white adipose tissue. If the storage capacity of adipose tissue is exceeded, lipids and other nutrients enter nonstorage tissues.
Muscle and liver are not well adapted to lipid storage, and lipid accumulation in these tissues is known as ectopic lipid accumulation.
TRUE or FALSE: The content of brown adipose tissue in humans is negatively correlated with age and positively correlated with obesity.
FALSE
The content of brown adipose tissue in humans is negatively correlated with (BOTH) age and obesity.
Brown adipose tissue is a thermogenic, energy-burning tissue that is activated by the sympathetic nervous system, which increases the mobilization and oxidation of fatty acids.
TRUE or FALSE: Prolonged or repeated cold exposure can increase the mass and activity of brown adipose tissue in the neck and supraclavicular regions, as defined by the uptake of glucose, and can improve glucose homeostasis.
TRUE
TRUE or FALSE: Increased muscle triglyceride content is inversely related to insulin-stimulated glucose uptake in muscle, but is not invariably linked to insulin resistance.
TRUE
Exercise training allows for improved lipid storage in muscle, thereby sequestering lipid intermediates and preventing fatty acid-induced insulin resistance, which is also seen with acute exercise.
TRUE or FALSE: In states of overfeeding and obesity, there can be activation of the unfolded protein response to alleviate endoplasmic reticulum workload, which leads to increased levels of endogenous inflammatory mediators, reduction in hepatic gluconeogenesis, etc, and, after prolonged activation, cellular dysfunction and apoptosis.
TRUE
TRUE or FALSE: Activation of the adaptive immune system in acute infection and obesity is associated with significant insulin resistance.
FALSE
INNATE immune system
Saturated FAs activate TLRs. PUFAs inhibit TLRs.
Proposed mechanism for the decrease in oxidative capacity seen in humans with insulin resistance, obesity, and T2DM.
- Insulin itself can upregulate mitochondrial biogenesis, and withdrawal of insulin in patients with T1DM leads to reductions in mitochondrial gene transcription and ATP synthesis.
- Sedentary lifestyle –> Reduced turnover of ATP and ATP synthesis –> Reduced ADP/ATP ratio and impairment of electron transport in the mitochondria –> Increased levels of reduced forms of NADH –> Impaired TCA cyle activity –> Generation of ROS due to elevated reducing pressure in the mitochondria
Primary site of glucose disposal after a meal:
a. Liver
b. Skeletal muscle
c. Adipocyte
d. Heart
B
(And primary mechanism of glucose storage is through its conversion to glycogen)
In obesity, insulin resistance in ___ is manifested before abnormalities in insulin signaling in the other tissues, possibly reflecting its relatively limited nutrient storage capacity.
a. Liver
b. Skeletal muscle
c. Adipocyte
B
Mechanism of insulin resistance in skeletal muscle
- Deficiency in nonoxidative disposal of glucose related primarily to a defect in glycogen synthesis, which itself is secondary to a decrease in insulin-stimulated glucose uptake.
- Increased fatty acid flux related to increased visceral lipolysis has been implicated in the inhibition of muscle glucose uptake, probably due to competition for substrate oxidation.
What is the Randle hypothesis?
Hypothesis that states that the basis of the reduction in insulin sensitivity seen with elevated fatty acids is the rise in intracellular glucose-6-phosphate concentrations (increased FA metabolism –> increased ratio of intramitochondrial acetyl-CoA to CoA and reduced NADH/NAD+ ratio –> Inhibition of pyruvate dehydrogenase –> Increased citrate concentrations and allosteric inhibition of phosphofructokinase, the key rate-controlling enzyme in glycolysis)
Key rate-controlling enzyme in glycolysis
Phosphofructokinase
Mechanism by which high-dose salicylate therapy can improve insulin sensitivity
By disruption of the IKK beta inflammatory pathway
3 families of proteins that mediate the uptake of fatty acid from the serum
1) fatty acid translocase
2) plasma membrane fatty acid-binding proteins (FABPs)
3) fatty acid transport proteins
Regulated by exercise, correlated with body weight (at least in women), and can be modulated by insulin infusion
Glucose effect on skeletal muscle fatty acid metabolism
Increased uptake of glucose –> Increased production of acetyl-CoA as product of glycolysis –> Increased TCA cycle activity and production of citrate –> Activation of acetyl-CoA carboxylase (ACC) and increased susceptibility to phosphatases (reduced phosphorylation) –>Acetyl-CoA converted to malonyl-CoA which is a potent inhibitor of palmitoyl-transferase (CPT) I on outer mitochondrial membrane –> Accumulation of fatty acyl-CoAs in cytoplasm –> Insulin resistance
Potent inhibitor of palmitoyl-transferase (CPT) I on outer mitochondrial membrane
Malonyl-CoA (elevated in humans with obesity or T2DM)
Drug that can reverse the effects of increased intracellular malonyl-CoA and its consequences in patients with obesity or T2DM
3-month treatment with insulin-sensitizer rosiglitazone
Effect of sleep disruption on carbohydrate metabolism
Experimental sleep disruption can directly impair insulin action, alter secretion of leptin and ghrelin resulting in stimulation of appetite, increase inflammatory cytokine production, and create alterations in other cardiovascular risk factors.
Role of gut microbiome and metabolome in diabetes and insulin resistance
The effects of the processes of the gut microbiome lead to tissue-specific metabolic dysregulation and immune activation, leading to insulin resistance and progression of diabetes pathogenesis. Metabolites such as 2-aminoadipate, alpha-hydroxybutyrate, and N-acetylglycine are suggested to be biomarkers.
Differentiate prebiotics from probiotics
Prebiotics - nutrients that change the composition of gut microbiota
Probiotics - mixtures of bacteria themselves
As the pregnancy progresses and insulin resistance builds, maternal insulin secretion increases by as much as ___% to compensate.
250%
Major risk factor for the development of gestational diabetes
Pre-pregnancy obesity
Driver of insulin resistance and beta cell expansion in pregnancy
Placenta-derived factors
Drugs Associated with Insulin Resistance
- Glucocorticoids
- HIV medications (all)
- Calcineurin inhibitors (tacrolimus and cyclosporine)
- Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus)
- Phophoinositide 3-kinase inhibitors
- Statins
Stressors Associated with Insulin Resistance
- Pregnancy
- Glucotoxicity
- Surgery
- Inflammation (from obesity or infection)
- Overnutrition
Rapid and long-term effects of glucocorticoids on carbohydrate metabolism
Rapid effects
- Increased hepatic glucose production via increased gluconeogenesis
- Acute insulin resistance in skeletal muscle
Long-term effects
- Redistribution of fat from the periphery to the central compartment
- Increased lipolysis and elevations in triglyceride and fatty acid
- Reduction in insulin secretion
TRUE or FALSE: Post-transplant diabetes mellitus (PTDM) is usually diagnosed within 10 days after transplant.
FALSE
Most patients become transiently hyperglycemic immediately post-transplant due to the stress of surgery and high doses of corticosteroids; thus, diagnosis of PTDM should not be made until the patient has been discharged from the hospital and is on a stable immunosuppressant dose.
TRUE or FALSE: HbA1c is usually used to diagnose post-transplant diabetes mellitus (PTDM).
FALSE
Consensus recommendations discourage the use of HbA1c for PTDM screening during the first year following transplant due to significant changes in RBC turnover.
Primary mechanism of glucocorticoids causing post-transplant DM
Induction of insulin resistance
Primary mechanism of mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, causing post-transplant DM
Induction of insulin resistance
Primary mechanism of calcineurin inhibitors, such as tacrolimus and cyclosporine, causing post-transplant DM
Decreased insulin secretion
How does insulin cause insulin resistance?
Increased inflammation in adipose tissue, including macrophage infiltration and increased cytokine expression (such as TNF alpha)
HIV medications that is primarily associated with lipoatrophy
Older thymidine analogue nucleoside reverse transcriptase inhibitors
Effect of protease inhibitors on carbohydrate metabolism
Inhibit glucose transport, possibly through interaction with the insulin-responsive GLUT4
Treatment of HIV-associated lipodystrophy
- Use of newer protease inhibitors
- Switching from thymidine analogues
- Treatment with thiazolidinediones
- TESORELIN - growth-hormone releasing hormone analogue, approved to treat abnormal lipids associated with HIV lipodystrophy, and causes a modest redistribution of visceral fat with subsequent improvement in the lipid profile
Growth-hormone releasing hormone analogue which is approved to treat abnormal lipids associated with HIV lipodystrophy, and causes a modest redistribution of visceral fat with subsequent improvement in the lipid profile
Tesorelin
TRUE or FALSE: Both lipoatrophy and lipohypertrophy are seen in HIV-infected patients on antiretroviral therapy.
TRUE
TRUE or FALSE: Statins do not cause an appreciable change in blood glucose in individual patients, but large clinical trials have demonstrated an increased risk for developing T2DM in patients treated with a statin.
TRUE
TRUE or FALSE: Hyperglycemia increases beta-cell function.
FALSE
Hyperglycemia itself can cause insulin resistance, as well as decreased beta-cell function.
Glucose metabolism pathway that, through its anti-insulin function, has been hypothesized to be a glucose sensor that allows the cell to sense and adapt to the prevailing level of glucose
Hexosamine pathway (such as glucosamine)
Aggressive treatment of postoperative hyperglycemia, with a target blood glucose of ____ mg/dL for both diabetic and nondiabetic patients, has been shown to reduce both wound infections and mortality following surgery.
140-180 mg/dL
Mechanisms by which epinephrine increases blood glucose
Decreased insulin secretion and increased insulin resistance both in muscle and in the liver (hence, adjustments in the insulin infusion rate are generally necessary due to the rapid and substantial impact of this medication)
